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Stimulus-Selective Response Plasticity in the Visual Cortex: An Assay for the Assessment of Pathophysiology and Treatment of Cognitive Impairment Associated with Psychiatric Disorders

  • Sam F. Cooke
    Affiliations
    Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts
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  • Mark F. Bear
    Correspondence
    Address correspondence to Mark Bear, Ph.D., Massachusetts Institute of Technology, The Picower Institute for Learning and Memory, Howard Hughes Medical Institute, 43 Vassar Street, 46-3301 Cambridge, MA 02139
    Affiliations
    Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts
    Search for articles by this author
      Long-term potentiation (LTP) is a form of experimentally induced enhancement of chemical synaptic transmission that has long been proposed as a model of the endogenous processes of synaptic plasticity that mediate memory. There is a large body of evidence that the molecular mechanisms underlying experimentally induced LTP also subserve various forms of naturally occurring, experience-dependent synaptic plasticity in animals and humans. Here we describe a phenomenon called stimulus-specific response potentiation (SRP), which occurs in the primary visual cortex of mice as a result of repeated exposure to visual stimuli and is believed to reveal the mechanisms that underlie perceptual learning. We first describe evidence that SRP represents naturally occurring LTP of thalamo-cortical synaptic transmission. We then discuss the potential value of SRP as a preclinical assay for the assessment of putative drug treatments on synaptic plasticity. Stimulus-specific response potentiation is not only easy to assay and robust but captures features of feed-forward glutamatergic function and visual learning that are deficient in human psychiatric disorders, notably including schizophrenia. We suggest that phenomena analogous to SRP in humans are likely to be useful biomarkers of altered cortical LTP and of treatment response in diseases associated with impaired cognition.

      Key Words

      Schizophrenia is a complex neurological disorder that affects approximately .5% of the global population directly (
      • Saha S.
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      • McGrath J.
      A systematic review of the prevalence of schizophrenia.
      ) and has a wider impact on society through huge sustained healthcare costs (
      • Wyatt R.J.
      • Henter I.
      • Leary M.C.
      • Taylor E.
      An economic evaluation of schizophrenia—1991.
      ). Symptoms of schizophrenia are separated into major clusters. These include positive, negative, and cognitive symptoms. Early descriptions of schizophrenia, initially designated dementia praecox, viewed the cognitive elements of the disorder as a central feature (
      • Javitt D.C.
      When doors of perception close: Bottom-up models of disrupted cognition in schizophrenia.
      ). Although available treatments have focused on positive symptoms or psychosis, there is now increased emphasis on tackling cognitive deficits in schizophrenia (
      • Butler P.D.
      • Silverstein S.M.
      • Dakin S.C.
      Visual perception and its impairment in schizophrenia.
      ), a domain of symptoms that contributes to poor functional outcome for sufferers of the disorder (
      • Green M.F.
      • Kern R.S.
      • Braff D.L.
      • Mintz J.
      Neurocognitive deficits and functional outcome in schizophrenia: Are we measuring the “right stuff”?.
      ,
      • McGurk S.R.
      • Mueser K.T.
      • Walling D.
      • Harvey P.D.
      • Meltzer H.Y.
      Cognitive functioning predicts outpatient service utilization in schizophrenia.
      ). Although it has long been held that schizophrenia results from functional disruption of particular brain regions, such as the prefrontal cortex and the hippocampus (
      • Volk D.W.
      • Lewis D.A.
      Prefrontal cortical circuits in schizophrenia.
      ,
      • Lisman J.E.
      • Coyle J.T.
      • Green R.W.
      • Javitt D.C.
      • Benes F.M.
      • Heckers S.
      • Grace A.A.
      Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia.
      ), broad-spectrum neuropsychological tests reveal that there is no greater impairment in any one brain region than another (
      • Javitt D.C.
      When doors of perception close: Bottom-up models of disrupted cognition in schizophrenia.
      ,
      • Heinrichs R.W.
      • Zakzanis K.K.
      Neurocognitive deficit in schizophrenia: A quantitative review of the evidence.
      ). Thus, overall pathophysiology of cognitive dysfunction cannot be attributed to a specific locus. Instead, deficits across the brain, including early in sensory processing, are likely to contribute different elements to the disorder.
      Deficits in visual learning have been observed in schizophrenic subjects (
      • Schretlen D.J.
      • Cascella N.G.
      • Meyer S.M.
      • Kingery L.R.
      • Testa S.M.
      • Munro C.A.
      • et al.
      Neuropsychological functioning in bipolar disorder and schizophrenia.
      ). These specific deficits might contribute to the cognitive symptoms of the disorder (
      • Green M.F.
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      • Kern R.S.
      • Baade L.E.
      • Fenton W.S.
      • Gold J.M.
      • et al.
      Functional co-primary measures for clinical trials in schizophrenia: Results from the MATRICS Psychometric and Standardization Study.
      ,
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      • Barch D.M.
      • Cohen J.D.
      • et al.
      The MATRICS Consensus Cognitive Battery, part 1: Test selection, reliability, and validity.
      ) but, regardless, could be exploited to reveal pathophysiological processes at the heart of the cognitive deficit. Human perceptual learning can be highly specific for features such as spatial frequency or orientation, suggesting that primary sensory cortex—in which these primitive features have not yet been integrated into invariant representations (
      • Gilbert C.D.
      • Sigman M.
      • Crist R.E.
      The neural basis of perceptual learning.
      )—is a site of underlying plasticity (
      • McNair N.A.
      • Clapp W.C.
      • Hamm J.P.
      • Teyler T.J.
      • Corballis M.C.
      • Kirk I.J.
      Spatial frequency-specific potentiation of human visual-evoked potentials.
      ,
      • Ross R.M.
      • McNair N.A.
      • Fairhall S.L.
      • Clapp W.C.
      • Hamm J.P.
      • Teyler T.J.
      • Kirk I.J.
      Induction of orientation-specific LTP-like changes in human visual evoked potentials by rapid sensory stimulation.
      ). Therefore understanding the synaptic basis of experience-dependent plasticity in primary visual cortex (V1) might provide insight into schizophrenia pathophysiology.
      Here we describe a simple, easy-to-assay form of stimulus-selective response potentiation (SRP) in the rodent that is well-understood at the molecular level. Stimulus-specific response potentiation is a manifestation, in part, of synaptic modification at the thalamocortical synapses in V1 and uses the mechanisms of canonical long-term potentiation (LTP). We suggest that the SRP assay in mice will enable interrogation of physiological mechanisms that might go awry in schizophrenia and other mental illnesses characterized by impaired cognitive function. Moreover, because it is a natural and functionally relevant manifestation of LTP, it enables assessment of the in vivo efficacy of potential treatments that target this mechanism.

      SRP

      Stimulus-specific response potentiation is long-lasting, experience-dependent plasticity that occurs in V1 of mice (Figure 1). In awake head-fixed animals, averaged visual evoked potentials (VEPs) driven by phase-reversing sinusoidal grating stimuli, recorded from layer 4 of binocular V1, undergo a gradual but striking increase in amplitude across days of repeated presentation of the same stimulus (
      • Frenkel M.Y.
      • Sawtell N.B.
      • Diogo A.C.
      • Yoon B.
      • Neve R.L.
      • Bear M.F.
      Instructive effect of visual experience in mouse visual cortex.
      ). Once expressed, SRP lasts for at least several weeks, and no evidence has yet been produced that it degrades with time, even in the absence of continued stimulus presentation. Alteration of stimulus properties, typically through changing orientation, reveals the specificity of the effect. Even stimuli rotated by as little as 5° from the familiar stimulus drive significantly lower amplitude VEPs (Figure 2A). Altering the spatial frequency (Figure 2B) or the contrast of the stimulus (Figure 2C) has a similar effect. Most remarkably, if the stimulus is presented to one eye only, SRP can be induced through this experienced eye without transfer to the inexperienced eye (Figures 2D–2F). This input specificity strongly suggests that plasticity underlying SRP occurs within layer 4, at thalamo-cortical synapses. At this stage of visual processing in the mouse visual cortex, eye-specific thalamic inputs converge on the same population of layer 4 target cells in the binocular zone (Figure 2E). This input specificity is reminiscent of LTP.
      Figure thumbnail gr1
      Figure 1Stimulus-specific response potentiation (SRP). (A) Visual-evoked potentials (VEPs) are recorded from both hemispheres of head-fixed, awake, male C57BL/6 mice and driven by full-field, high-contrast, phase-reversing sinusoidal grating stimuli. Electrodes are positioned in layer 4 of the binocular region of primary visual cortex (V1). (B) Diagram describing the time-course of a typical SRP experiment. Each block represents a day. Under anesthesia, animals receive implantation bilaterally with recording electrodes, and a headpost is affixed. They are then allowed to recover overnight, before receiving 2 half-hour habituation sessions in front of a gray screen during the following 2 days. On the next day, experimental day 1, a first oriented stimulus is presented (X°), and an averaged VEP resulting from 400 phase reversals is generated. This procedure is then repeated over the next 4 experimental days. On experimental day 5 this now-familiar stimulus is presented and, interleaved, a novel X+45° stimulus is also presented. This novel stimulus is then presented over the following 4 days, and VEPs are collected before finally testing VEP amplitude driven by 3 stimuli, the two familiar X and X+45° orientations and a novel X+90° stimulus. (C) The phenomenon of SRP can be seen in the gradual enhancement in VEP amplitude across days. The SRP develops over 5 days to X°, and orientation specificity is revealed as the VEP falls back to basal amplitude when the X+45° stimulus is presented. The SRP then develops with a similar temporal profile to the novel stimulus. Returning to the original X° stimulus, even without presentation during the intervening 4 days, reveals maintained VEP amplitude potentiation. Stimulus specificity continues to be apparent with each presentation of a novel stimulus as the VEP falls back to basal amplitude. Scale bars are 100 μV vertically and 50 μsec horizontally (data re-presented from [
      • Frenkel M.Y.
      • Sawtell N.B.
      • Diogo A.C.
      • Yoon B.
      • Neve R.L.
      • Bear M.F.
      Instructive effect of visual experience in mouse visual cortex.
      ]). Contra, contralateral; Ipsi, ipsilateral.
      Figure thumbnail gr2
      Figure 2SRP specificity. (A) The SRP is exquisitely specific for orientation, as revealed by the fact that, on day 5 after saturated SRP to a now-familiar orientation (dark gray square), VEP amplitude drops significantly back toward basal values with a novel (Nov) stimulus (dark gray circles) shifted by just 5° from the familiar (Fam) orientation. If the shift in orientation is gradually increased, it can be seen that a novel stimulus shifted by approximately 25°–30° from familiar will evoke a VEP of basal amplitude. (B) The SRP is also specific for spatial frequency in that repeated binocular exposure to a .05 cycle/° grating of a particular orientation (dark gray squares) results in SRP only to that spatial frequency with no significant gains over a novel orientation (dark gray circles) at other spatial frequencies. (C) The same is true for contrast. The SRP at 100% contrast shows no transfer to other contrasts (data re-presented from [
      • Cooke S.F.
      • Bear M.F.
      Visual experience induces long-term potentiation in the primary visual cortex.
      ], with permission from Nature Publishing Group). (D) An occluding paddle can be used to selectively block the presentation of the visual stimulus to one or the other eye of the headfixed mouse preparation and thereby test VEP amplitudes selectively evoked with binocular (dark gray), Contralateral (black), or Ipsilateral (light gray)-only stimulus presentation. (E) In the rodent visual cortex, thalamo-recipient cells—predominantly in layer 4 but also found in other layers—are usually responsive to independent inputs from either eye. This feature of the system enables testing of whether SRP transfers from an experienced eye to an inexperienced eye. (F) The SRP is revealed to be eye-specific. Presentation of two different stimuli (circle or square) to only the Ipsilateral (light gray) or only the Contralateral eye (black) on experimental day 1 allows for determination of basal VEP amplitude. In this case only the Ipsilateral eye then experiences repeated presentation of the same stimulus over subsequent days until a final test day when stimulus-specificity is tested by reversing the configuration of stimulus presentation to each eye that was seen on day 1, such that both eyes view a novel stimulus. There is no transfer of SRP from the Ipsilateral to the Contralateral eye (data re-presented from [
      • Frenkel M.Y.
      • Sawtell N.B.
      • Diogo A.C.
      • Yoon B.
      • Neve R.L.
      • Bear M.F.
      Instructive effect of visual experience in mouse visual cortex.
      ], with permission from Elsevier, copyright 2006). Rec., recording electrode(s); TC, thalamo-cortical; other abbreviations as in .

      LTP

      Long-term potentiation is a phenomenon in which chemical synaptic transmission is enhanced in a lasting fashion through co-incident pre- and post-synaptic activity. It has several properties that make it an attractive candidate memory mechanism. First, LTP has been demonstrated to last for several months under the right conditions, revealing that it has the longevity required of a storage device (
      • Abraham W.C.
      • Logan B.
      • Greenwood J.M.
      • Dragunow M.
      Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus.
      ). Second, it is input-specific: only active synapses contacting a depolarizing cell undergo LTP, whereas nearby inactive neighboring synapses remain unchanged in strength (Figure 3). Third, it is both associative and cooperative (
      • McNaughton B.L.
      Long-term potentiation, cooperativity and Hebb's cell assemblies: A personal history.
      ). Thus, weakly active synapses, themselves not strong enough to drive post-synaptic depolarization, can undergo potentiation if associated in time with activity in other inputs that cooperate to depolarize the post-synaptic target cell (
      • McNaughton B.L.
      • Douglas R.M.
      • Goddard G.V.
      Synaptic enhancement in fascia dentata: Cooperativity among coactive afferents.
      ,
      • Barrionuevo G.
      • Brown T.H.
      Associative long-term potentiation in hippocampal slices.
      ,
      • Andersen P.
      • Sundberg S.H.
      • Sveen O.
      • Swann J.W.
      • Wigström H.
      Possible mechanisms for long-lasting potentiation of synaptic transmission in hippocampal slices from guinea-pigs.
      ). These properties all fulfill criteria intimated by Donald Hebb in his influential text “The Organization of Behavior” (
      • Hebb D.O.
      The Organization of Behavior.
      ) when describing the theoretical constraints of a synaptic memory mechanism in the brain, leading to comparable forms of plasticity commonly being described as “Hebbian.”
      Figure thumbnail gr3
      Figure 3Canonical long-term potentiation (LTP). (A) The transverse hippocampal slice has been the favored preparation for studying LTP, due to its beautifully simple laminated structure, the presence of a single layer of excitatory cells organized as a perfect dipole, and its overall robustness ex vivo. The synapse between Schaffer collateral (Sch) fibers originating from pyramidal cells in the CA3 subfield, either ipsilaterally or contralaterally via commissural fibers (comm.), and pyramidal cells in the CA1 subfield has served as a primary focus of LTP research; and the molecular mechanisms of induction, expression, and maintenance are now described as canonical. Very different mechanisms are thought to underlie mossy fiber (mf)-CA3 LTP and will not be discussed here. The LTP at synapses between the perforant path (pp), originating in the entorhinal cortex (EC), and granule cells of the dentate gyrus (DG) were the first to be studied, and the mechanisms are broadly similar to the canonical LTP described here. Visualization of the slice allows for placement of two stimulating electrodes (Stim.) in pathways that independently contact the same population of post-synaptic pyramidal cells—here described as input 1 and 2. (B) This organization has enabled researchers to demonstrate the input-specificity of LTP, here revealed as enhancement of the excitatory postsynaptic potential (EPSP) slope of population field potentials recorded in the dendritic zone of CA1, selectively in the tetanized input (black circles), which receives high-frequency stimulation (HFS) without impact on the untetanized control pathway (open circles), which receives just low-frequency stimulation. The LTP can be maintained over many hours if the appropriate induction protocol is used. Scale bar is 1 mV vertically and 5 msec horizontally. (C) Similar molecular mechanisms are believed to support LTP at TC synapses. Again, the ex vivo slice preparation has been critical in identifying molecular mechanisms, although in this case the structure is primary visual cortex. Several synapses can be studied in this preparation, but here we focus on the TC input from the thalamus to layer 4 and layer 2/3. Stimulation of the white matter containing TC fibers evokes population field potential responses recorded in layer 4 and layer 2/3. (D) The LTP can be induced at these synapses with θ burst stimulation (TBS), resulting in a potentiation of the amplitude of the field potential. Field potential amplitude rather than EPSP slope is used as a proxy for synaptic potentiation, because pure dendritic field potentials cannot be isolated in this multi-laminar structure. Scale bar is 1 mV vertically and 10 msec horizontally (plot adapted from [
      • Kirkwood A.
      • Lee H.K.
      • Bear M.F.
      Co-regulation of long-term potentiation and experience-dependent synaptic plasticity in visual cortex by age and experience.
      ], with permission from Nature Publishing Group). (E) Canonical LTP mechanisms center on the N-methyl-D-aspartate receptor (NMDAR) and the influx of calcium (Ca2+) through that receptor as a result of both pre-synaptic glutamate release and post-synaptic depolarization, predominantly mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid class of glutamate receptor (AMPAR) conductance of cations. The Ca2+ influx initiates kinase and phosphatase activity, the balance of which determines whether LTP is expressed. Expression mechanisms include post-translational modification (phosphorylation) of existing AMPARs by calcium-dependent kinases to enhance conductance and the introduction of new AMPARs into the post-synaptic membrane. There also exist pre-synaptic expression mechanisms that lead to an enhancement of glutamate release. Pre-synaptic expression mechanisms require the existence of a retrograde signal for which several candidates have been identified. For maintenance of LTP beyond a few hours there is a requirement for the synthesis of new proteins, through both local translation and transcription of RNA at the nucleus. Again, a signal from the synapse to the nucleus is required for this de novo synthesis to occur, and evidence suggests that a signaling cascade is initiated by sustained calcium influx that activates kinases such as CaMKII, PKA, and PKC. The resultant newly expressed LTP effector proteins are believed to participate in further stabilization of new AMPAR insertion and structural plasticity, resulting in growth of the synapse both pre- and post-synaptically. Mg2+, magnesium dimer; Na+, sodium cation.
      Long-term potentiation was initially induced by applying a high-frequency train of electrical pulses or “tetanus” to an afferent pathway in the hippocampus (
      • Bliss T.V.
      • Lomo T.
      Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path.
      ). This tetanus ensured coincident pre- and postsynaptic depolarization and resulted in a lasting enhancement of synaptic strength, as revealed by measuring the slope of the excitatory postsynaptic potential (EPSP) component of electrically evoked population field potentials. The same phenomenon has since been observed in awake, freely moving animals and monitored for many days, weeks, and even months (
      • Abraham W.C.
      • Logan B.
      • Greenwood J.M.
      • Dragunow M.
      Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus.
      ,
      • Bliss T.V.
      • Gardner-Medwin A.R.
      Long-lasting potentiation of synaptic transmission in the dentate area of the unanaestetized rabbit following stimulation of the perforant path.
      ,
      • Cooke S.F.
      • Wu J.
      • Plattner F.
      • Errington M.
      • Rowan M.
      • Peters M.
      • et al.
      Autophosphorylation of alphaCaMKII is not a general requirement for NMDA receptor-dependent LTP in the adult mouse.
      ). Long-term potentiation has also been identified at most synapses in the nervous system and across many species (
      • Malenka R.C.
      • Bear M.F.
      LTP and LTD: An embarrassment of riches.
      ). The development of the transverse hippocampal slice (
      • Skrede K.K.
      • Westgaard R.H.
      The transverse hippocampal slice: A well-defined cortical structure maintained in vitro.
      ), an ex vivo preparation that allows for precisely timed pharmacological treatment, has enabled a careful dissection of the biochemical/biophysical mechanisms of LTP. More recently, genetic manipulations have augmented this approach by increasing the specificity and degree of intervention. With the Schaffer collateral-CA1 pyramidal cell synapse as a model, mechanisms of LTP-induction, expression, and maintenance have been determined (Figure 3E). Many of these mechanisms are shared across synapses in the nervous system, including in V1 (Figures 3C and 3D), and can be described as canonical, although it is important to remember that characteristics of LTP do vary regionally (
      • Malenka R.C.
      • Bear M.F.
      LTP and LTD: An embarrassment of riches.
      ). Recent work with genetically modified animals and in vivo pharmacology has demonstrated commonalities between molecular mechanisms of LTP and memory (see [
      • Martin S.J.
      • Grimwood P.D.
      • Morris R.D.
      Synaptic plasticity and memory: An evaluation of the hypothesis.
      ,
      • Neves G.
      • Cooke S.F.
      • Bliss T.V.
      Synaptic plasticity, memory and the hippocampus: A neural network approach to causality.
      ] for review).
      Long-term potentiation-like effects can also be induced in the brain through sensory experience. In the hippocampus, synaptic potentiation develops concurrently with two forms of memory; trace eyeblink conditioning (
      • Gruart A.
      • Munoz M.D.
      • Delgado-Garcia J.M.
      Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice.
      ) and inhibitory avoidance (
      • Whitlock J.R.
      • Heynen A.J.
      • Shuler M.G.
      • Bear M.F.
      Learning induces long-term potentiation in the hippocampus.
      ). Both of these forms of memory require intact hippocampal circuitry, and both depend on molecular mechanisms shared with LTP (
      • Sakamoto T.
      • Takatsuki K.
      • Kawahara S.
      • Kirino Y.
      • Niki H.
      • Mishina M.
      Role of hippocampal NMDA receptors in trace eyeblink conditioning.
      ,
      • Walker D.L.
      • Gold P.E.
      Effects of the novel NMDA antagonist, NPC 12626, on long-term potentiation, learning and memory.
      ). Enhancements in synaptic strength occur in the amygdala during two forms of learning: fear conditioning (
      • Sacchetti B.
      • Lorenzini C.A.
      • Baldi E.
      • Bucherelli C.
      • Roberto M.
      • Tassoni G.
      • Brunelli M.
      Long-lasting hippocampal potentiation and contextual memory consolidation.
      ,
      • Doyère V.
      • Debiec J.
      • Monfils M.H.
      • Schafe G.E.
      • LeDoux J.E.
      Synapse-specific reconsolidation of distinct fear memories in the lateral amygdala.
      ), and operant reward conditioning (
      • Tye K.M.
      • Stuber G.D.
      • de Ridder B.
      • Bonci A.
      • Janak P.H.
      Rapid strengthening of thalamo-amygdala synapses mediates cue-reward learning.
      ). In the motor cortex, LTP-like plasticity can be observed after motor learning in rats (
      • Rioult-Pedotti M.S.
      • Friedman D.
      • Donoghue J.P.
      Learning-induced LTP in neocortex.
      ). Most importantly, experience-dependent plasticity occludes the subsequent induction of LTP, both ex vivo (
      • Rioult-Pedotti M.S.
      • Friedman D.
      • Donoghue J.P.
      Learning-induced LTP in neocortex.
      ) and in vivo (
      • Whitlock J.R.
      • Heynen A.J.
      • Shuler M.G.
      • Bear M.F.
      Learning induces long-term potentiation in the hippocampus.
      ), demonstrating shared core mechanisms. These experiments have all been important in establishing a causal relationship between LTP-like plasticity and memory in the central nervous system, although it has still not been proven that synaptic potentiation is both necessary and sufficient for memory (
      • Martin S.J.
      • Grimwood P.D.
      • Morris R.D.
      Synaptic plasticity and memory: An evaluation of the hypothesis.
      ,
      • Neves G.
      • Cooke S.F.
      • Bliss T.V.
      Synaptic plasticity, memory and the hippocampus: A neural network approach to causality.
      ) or, most importantly, exactly how synaptic plasticity is implemented at a circuit and systems level.

      Is SRP an Endogenous Form of LTP?

      Evidence for a causal relationship between LTP and SRP comes from in vivo experiments in which thalamo-cortical LTP is induced by delivery of an electrical tetanus to the dorsal lateral geniculate nucleus. This form of LTP, as initially assessed with electrically evoked field potentials, also enhances the amplitude of VEPs in anesthetized rats (
      • Heynen A.J.
      • Bear M.F.
      Long-term potentiation of thalamocortical transmission in the adult visual cortex in vivo.
      ), indicating that electrical stimulation can have a lasting potentiating influence on sensory processing. This observation has since been replicated by others in the visual cortex (
      • Kuo M.C.
      • Dringenberg H.C.
      Short-term (2 to 5 h) dark exposure lowers long-term potentiation (LTP) induction threshold in rat primary visual cortex.
      ,
      • Hager A.M.
      • Dringenberg H.C.
      Training-induced plasticity in the visual cortex of adult rats following visual discrimination learning.
      ) and auditory cortex (
      • Hogsden J.L.
      • Dringenberg H.C.
      NR2B subunit-dependent long-term potentiation enhancement in the rat cortical auditory system in vivo following masking of patterned auditory input by white noise exposure during early postnatal life.
      ). Similar LTP can be induced in the mouse, and it has been possible to use the principles of mimicry and occlusion to test the effects of LTP on the subsequent induction of SRP (
      • Cooke S.F.
      • Bear M.F.
      Visual experience induces long-term potentiation in the primary visual cortex.
      ) (Figure 4). In the mouse, just as in the rat, the amplitude of both the electrically evoked field potential and the VEP is significantly enhanced by the induction of thalamo-cortical LTP in a single hemisphere. The LTP occludes the subsequent development of SRP in this hemisphere, whereas SRP develops normally in the opposite control hemisphere that has not undergone LTP (Figure 4C). The occlusion of SRP by LTP is mutual, as demonstrated by inducing SRP to a single orientation before LTP. The VEPs driven by this familiar stimulus do not undergo LTP. Due to the stimulus specificity of SRP, it is possible to also show a novel stimulus both before and after LTP and demonstrate, in the same animals and same recording sessions, that VEPs are potentiated by LTP only if the stimulus is novel (Figure 4D). Thus, all the available evidence, both correlative and interventional, indicates that SRP and LTP use the same processes and that SRP can be regarded as a proxy for N-methyl-D-aspartate receptor (NMDAR)-dependent feedforward excitatory synaptic plasticity.
      Figure thumbnail gr4
      Figure 4SRP as LTP. (A) LTP can be induced at thalamo-cortical synapses with an acutely placed stimulating electrode in the dorsal lateral geniculate nucleus (dLGN) under light isoflurane anesthesia. Field potentials can be recorded in layer 4 of V1 through the same recording electrode, whether driven by an electrical pulse to the dLGN in the anesthetized mouse or by a phase reversal of a visual stimulus in the awake animal. Experiments could then be conducted to assess interactions between SRP and LTP with one hemisphere undergoing LTP (black) and the opposite hemisphere serving as a control receiving a single electrical pulse every 30 sec (white). (B) Electrically evoked TC field potentials recorded in layer 4 underwent significant LTP after three trains of TBS were applied with a 5-min inter-burst interval. The LTP of field potential amplitude lasted for at least 1 hour before the stimulating electrode was removed and the animal recovered from anesthesia. Scale bar is 1 mV vertically and 5 msec horizontally. (C) The LTP mimics SRP in enhancing VEP amplitude in the tetanized hemisphere (black circles) significantly compared with VEPs in the control hemisphere (white circles) immediately upon recovery from anesthesia. The SRP is also significantly occluded because, by day 5, VEPs are of equivalent amplitude in both hemispheres, with those in the untetanized hemisphere undergoing significantly more SRP than in the tetanized hemisphere. (D) The complementary experiment reveals that the occlusion effect is bidirectional, such that TBS delivery enhances VEP amplitude in a separate group of mice after SRP has already been saturated. However, the mimicry effect is only seen for VEPs driven by novel stimuli (black circles) and not for those driven by familiar stimuli (black squares), due to occlusion by prior SRP. Thus VEPs driven by a familiar stimulus are significantly greater amplitude than those driven by a novel stimulus before TBS delivery but no longer different after TBS delivery. Scale bar is 100 μV vertically and 50 msec horizontally (adapted from [
      • Cooke S.F.
      • Bear M.F.
      Visual experience induces long-term potentiation in the primary visual cortex.
      ], with permission from Nature Publishing Group). Other abbreviations as in Figure 1, Figure 2, Figure 3.
      We hasten to add, however, that VEP amplitude undergoes much greater potentiation through experience or electrical stimulation than electrically evoked potentials do during in vivo LTP experiments. Thus, the effects of simple Hebbian synaptic plasticity are amplified when the VEP is generated by a visual stimulus. Further experiments will be required to fully understand this amplification process. It is interesting to consider the possibility that inhibitory interneurons might play a significant role. In any case, although we can conclude that SRP uses the mechanisms of LTP, the mechanisms of LTP are not sufficient to account for the full expression of SRP.
      The behavioral significance of SRP has not yet been established. In many ways the phenomenon is reminiscent of perceptual learning, a long-studied form of plasticity that results in improved stimulus detection (
      • Gilbert C.D.
      • Sigman M.
      • Crist R.E.
      The neural basis of perceptual learning.
      ). Many forms of visual perceptual learning are extremely specific for stimulus properties and sometimes do not show interocular transfer (
      • Fiorentini A.
      • Berardi N.
      Perceptual learning specific for orientation and spatial frequency.
      ,
      • Poggio T.
      • Fahle M.
      • Edelman S.
      Fast perceptual learning in visual hyperacuity.
      ), leading researchers to hypothesize that underlying plasticity occurs in V1 itself (
      • Schoups A.A.
      • Vogels R.
      • Orban G.A.
      Human perceptual learning in identifying the oblique orientation: Retinotopy, orientation specificity and monocularity.
      ). Indeed, perceptual learning results in increased neural responsiveness of V1 in humans (
      • Furmanski C.S.
      • Schluppeck D.
      • Engel S.A.
      Learning strengthens the response of primary visual cortex to simple patterns.
      ) and other species (
      • Schoups A.
      • Vogels R.
      • Qian N.
      • Orban G.
      Practising orientation identification improves orientation coding in V1 neurons.
      ). Another key element of perceptual learning is that it can occur in the absence of explicit reward or attention (
      • Watanabe T.
      • Náñez Sr, J.E.
      • Koyama S.
      • Mukai I.
      • Liederman J.
      • Sasaki Y.
      Greater plasticity in lower-level than higher-level visual motion processing in a passive perceptual learning task.
      ,
      • Watanabe T.
      • Nanez J.E.
      • Sasaki Y.
      Perceptual learning without perception.
      ), just as SRP evolves through passive viewing.
      A long-standing hypothesis holds that LTP-like synaptic plasticity mediates perceptual learning in V1 (
      • Hebb D.O.
      The Organization of Behavior.
      ). Recent work has shown that VEP amplitude increases in V1 of rats after perceptual learning in a watermaze (
      • Hager A.M.
      • Dringenberg H.C.
      Training-induced plasticity in the visual cortex of adult rats following visual discrimination learning.
      ,
      • Sale A.
      • De Pasquale R.
      • Bonaccorsi J.
      • Pietra G.
      • Olivieri D.
      • Berardi N.
      • Maffei L.
      Visual perceptual learning induces long-term potentiation in the visual cortex.
      ), although in these cases learning was accompanied by the reward of finding an escape from water. Thus, perceptual learning seems to enhance the strength of V1 synapses, although results are somewhat inconsistent. One study reports a subsequent occlusion of LTP at intra-cortical synapses (
      • Sale A.
      • De Pasquale R.
      • Bonaccorsi J.
      • Pietra G.
      • Olivieri D.
      • Berardi N.
      • Maffei L.
      Visual perceptual learning induces long-term potentiation in the visual cortex.
      ), and the other reports an enhancement of LTP as a result of experience in the watermaze (
      • Hager A.M.
      • Dringenberg H.C.
      Training-induced plasticity in the visual cortex of adult rats following visual discrimination learning.
      ), possibly suggesting some form of priming or metaplasticity (
      • Abraham W.C.
      Metaplasticity: Tuning synapses and networks for plasticity.
      ,
      • Abraham W.C.
      • Bear M.F.
      Metaplasticity: The plasticity of synaptic plasticity.
      ). These contrasting findings reveal the added complexity of including explicit reward in the experience of the animal. It is known, for example, that synaptic plasticity can occur in V1 as a result of reward (
      • Shuler M.G.
      • Bear M.F.
      Reward timing in the primary visual cortex.
      ).
      There are several reports in both animals and humans that LTP-like plasticity can be induced in V1 with a photic tetanus, in which flashing or phase reversing visual stimuli are presented at a frequency sufficiently high to induce an immediate enhancement of VEP amplitude (
      • McNair N.A.
      • Clapp W.C.
      • Hamm J.P.
      • Teyler T.J.
      • Corballis M.C.
      • Kirk I.J.
      Spatial frequency-specific potentiation of human visual-evoked potentials.
      ,
      • Ross R.M.
      • McNair N.A.
      • Fairhall S.L.
      • Clapp W.C.
      • Hamm J.P.
      • Teyler T.J.
      • Kirk I.J.
      Induction of orientation-specific LTP-like changes in human visual evoked potentials by rapid sensory stimulation.
      ,
      • Clapp W.C.
      • Eckert M.J.
      • Teyler T.J.
      • Abraham W.C.
      Rapid visual stimulation induces N-methyl-D-aspartate receptor-dependent sensory long-term potentiation in the rat cortex.
      ). Clapp and Teyler (
      • Clapp W.C.
      • Teyler T.J.
      Translating long-term potentiation from animals to humans: A novel method for non-invasive assessment of cortical plasticity.
      ) will discuss this phenomenon at greater length in an accompanying article within this issue. Here they reveal, importantly, that photic-tetanus-induced potentiation is accompanied by an improvement in detection of stimuli at low luminance, demonstrating that this form of plasticity has some behavioral utility. We would like to point out that there are both similarities and differences between SRP and this tetanus-induced LTP. The most striking similarities are, first, that molecular mechanisms seem to be shared (
      • Clapp W.C.
      • Eckert M.J.
      • Teyler T.J.
      • Abraham W.C.
      Rapid visual stimulation induces N-methyl-D-aspartate receptor-dependent sensory long-term potentiation in the rat cortex.
      ), and second, that both are specific for orientation and spatial frequency (
      • McNair N.A.
      • Clapp W.C.
      • Hamm J.P.
      • Teyler T.J.
      • Corballis M.C.
      • Kirk I.J.
      Spatial frequency-specific potentiation of human visual-evoked potentials.
      ,
      • Ross R.M.
      • McNair N.A.
      • Fairhall S.L.
      • Clapp W.C.
      • Hamm J.P.
      • Teyler T.J.
      • Kirk I.J.
      Induction of orientation-specific LTP-like changes in human visual evoked potentials by rapid sensory stimulation.
      ). In the future, it will be interesting to test whether these two forms of plasticity mutually occlude one another. An obvious difference that exists between SRP and the effects of tetanic stimulation, either photic or electrical, is that SRP takes several hours to impact VEP amplitude, whereas tetanus-induced LTP expresses itself almost immediately. This delayed manifestation of SRP suggests a requirement for some kind of consolidation process, potentially involving sleep (
      • Ji D.
      • Wilson M.A.
      Coordinated memory replay in the visual cortex and hippocampus during sleep.
      ,
      • Rolls A.
      • Colas D.
      • Adamantidis A.
      • Carter M.
      • Lanre-Amos T.
      • Heller H.C.
      • de Lecea L.
      Optogenetic disruption of sleep continuity impairs memory consolidation.
      ). It will be important to characterize this process. It is possible that behavioral modifications accompanying SRP might be delayed in a similar fashion, in keeping with a causal role for the plasticity in visual learning.

      Molecular Mechanisms of LTP and SRP

      We will not discuss the molecular mechanisms of canonical LTP in great depth, because it is beyond the scope of this review, but we will introduce important features that are shared with SRP.
      The detection of coincident activity pre- and post-synaptically—such a key feature of canonical Hebbian LTP—requires the NMDA class of glutamate receptor (
      • Collingridge G.L.
      • Kehl S.J.
      • McLennan H.
      Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.
      ,
      • Harris E.W.
      • Ganong A.H.
      • Cotman C.W.
      Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors.
      ). The NMDAR is both ionotropic and voltage-dependent. This means that glutamate must be present to open the receptor ion channel, indicative of pre-synaptic activity and transmitter release, and the post-synaptic membrane must also be depolarized to remove a blocking magnesium ion from the channel (
      • Nowak L.
      • Bregestovski P.
      • Ascher P.
      • Herbet A.
      • Prochiantz A.
      Magnesium gates glutamate-activated channels in mouse central neurones.
      ). If both of these events occur, then there is a large cation influx through the receptor channel, notably of calcium, and the induction mechanisms of LTP are initiated (
      • Lynch G.
      • Larson J.
      • Kelso S.
      • Barrionuevo G.
      • Schottler F.
      Intracellular injections of EGTA block induction of hippocampal long-term potentiation.
      ,
      • Malenka R.C.
      • Kauer J.A.
      • Zucker R.S.
      • Nicoll R.A.
      Postsynaptic calcium is sufficient for potentiation of hippocampal synaptic transmission.
      ). Several calcium-dependent kinases are then activated in response to the elevated levels of calcium and phosphorylate target substrates within the synapse that participate in the expression of LTP (
      • Giese K.P.
      • Fedorov N.B.
      • Filipkowski R.K.
      • Silva A.J.
      Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning.
      ,
      • Abel T.
      • Nguyen P.V.
      • Barad M.
      • Deuel T.A.
      • Kandel E.R.
      • Bourtchouladze R.
      Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory.
      ,
      • Malenka R.C.
      • Madison D.V.
      • Nicoll R.A.
      Potentiation of synaptic transmission in the hippocampus by phorbol esters.
      ). The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid class of glutamate receptor (AMPAR), which mediates the majority of fast excitatory transmission in the central nervous system, is notable amongst these targets. Phosphorylation of the receptor at key residues alters its conformation and enhances its function (
      • Greengard P.
      • Jen J.
      • Nairn A.C.
      • Stevens C.F.
      Enhancement of the glutamate response by cAMP-dependent protein kinase in hippocampal neurons.
      ,
      • Wang L.Y.
      • Dudek E.M.
      • Browning M.D.
      • MacDonald J.F.
      Modulation of AMPA/kainate receptors in cultured murine hippocampal neurones by protein kinase C.
      ,
      • Barria A.
      • Muller D.
      • Derkach V.
      • Griffith L.C.
      • Soderling T.R.
      Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation.
      ). New AMPARs are also inserted into the post-synaptic membrane to increase the effect of glutamate post-synaptically (
      • Malinow R.
      AMPA receptor trafficking and long-term potentiation.
      ). In its early phase, LTP does not require the synthesis of new proteins. However, after an hour or so there is a requirement for new proteins at the synapse if LTP is to be maintained (
      • Frey U.
      • Krug M.
      • Reymann K.G.
      • Matthies H.
      Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro.
      ,
      • Otani S.
      • Marshall C.J.
      • Tate W.P.
      • Goddard G.V.
      • Abraham W.C.
      Maintenance of long-term potentiation in rat dentate gyrus requires protein synthesis but not messenger RNA synthesis immediately post-tetanization.
      ). One of the newly synthesized proteins that plays a critical role in LTP maintenance is the calcium-dependent protein kinase isoform, PKMζ (
      • Sacktor T.C.
      How does PKMzeta maintain long-term memory?.
      ). This enzyme is unusual in that it has no auto-regulatory domain and does not require elevated calcium to remain active. It is believed to maintain LTP for long periods of time by preventing AMPAR removal from the post-synaptic membrane (
      • Migues P.V.
      • Hardt O.
      • Wu D.C.
      • Gamache K.
      • Sacktor T.C.
      • Wang Y.T.
      • Nader K.
      PKMzeta maintains memories by regulating GluR2-dependent AMPA receptor trafficking.
      ). There are a wide range of other LTP induction and expression mechanisms, including pre-synaptic effects that increase transmitter release and changes in the structure of the synapse, but we do not provide any detail about those here, because it is not within the scope of this review (for further reading see [
      • Errington M.L.
      • Galley P.T.
      • Bliss T.V.
      Long-term potentiation in the dentate gyrus of the anaesthetized rat is accompanied by an increase in extracellular glutamate: Real-time measurements using a novel dialysis electrode.
      ,
      • Zalutsky R.A.
      • Nicoll R.A.
      Comparison of two forms of long-term potentiation in single hippocampal neurons.
      ]).
      The results of experimental interventions strongly suggest that SRP represents an LTP-like process. Systemic application of the competitive NMDAR antagonist 3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) before each stimulus-exposure prevents the development of SRP, just as has been observed for visual cortical LTP (
      • Kirkwood A.
      • Dudek S.M.
      • Gold J.T.
      • Aizenman C.D.
      • Bear M.F.
      Common forms of synaptic plasticity in the hippocampus and neocortex in vitro.
      ) (Figures 5A and 5B). Importantly, genetic ablation of the NMDAR selectively in glutamatergic cells of the cortex also prevents the induction of SRP, demonstrating that SRP results from plasticity at synapses on these excitatory neurons (
      • Chang A.B.
      Critical requirements for NMDA receptors in experience-dependent plasticity in the visual cortex [thesis].
      ). Local blockade of AMPAR insertion with a peptide that mimics the cytoplasmic tail of AMPARs and thereby exerts a dominant-negative effect on insertion prevents SRP (
      • Frenkel M.Y.
      • Sawtell N.B.
      • Diogo A.C.
      • Yoon B.
      • Neve R.L.
      • Bear M.F.
      Instructive effect of visual experience in mouse visual cortex.
      ) (Figures 5A and 5C), just as canonical LTP is blocked by the same treatment (
      • Shi S.
      • Hayashi Y.
      • Esteban J.A.
      • Malinow R.
      Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons.
      ). Local delivery of ζ-inhibitory peptide (ZIP), a peptide that specifically inhibits PKMζ and erases both cortex-dependent memory (
      • Shema R.
      • Sacktor T.C.
      • Dudai Y.
      Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKM zeta.
      ) and canonical LTP (
      • Pastalkova E.
      • Serrano P.
      • Pinkhasova D.
      • Wallace E.
      • Fenton A.A.
      • Sacktor T.C.
      Storage of spatial information by the maintenance mechanism of LTP.
      ), erases established SRP (
      • Cooke S.F.
      • Bear M.F.
      Visual experience induces long-term potentiation in the primary visual cortex.
      ) (Figures 5A and 5D). One key fact that comes out of such experiments is that SRP can be prevented by local treatment in V1. Blockade of AMPARs (
      • Frenkel M.Y.
      • Sawtell N.B.
      • Diogo A.C.
      • Yoon B.
      • Neve R.L.
      • Bear M.F.
      Instructive effect of visual experience in mouse visual cortex.
      ) or of PKMζ (
      • Cooke S.F.
      • Bear M.F.
      Visual experience induces long-term potentiation in the primary visual cortex.
      ), restricted to the recording site, can prevent SRP induction or maintenance, respectively. Thus, plasticity subserving SRP occurs in V1 and is not an echo of events occurring elsewhere in the brain. The VEP comprises synaptic events (
      • Porciatti V.
      • Pizzorusso T.
      • Maffei L.
      The visual physiology of the wild type mouse determined with pattern VEPs.
      ) that occur local to the recording site (
      • Katzner S.
      • Nauhaus I.
      • Benucci A.
      • Bonin V.
      • Ringach D.L.
      • Carandini M.
      Local origin of field potentials in visual cortex.
      ), so SRP likely represents LTP-like plasticity of thalamo-cortical synapses in layer 4. Nevertheless, there is evidence that intra-cortical plasticity occurs through perceptual learning (
      • Sale A.
      • De Pasquale R.
      • Bonaccorsi J.
      • Pietra G.
      • Olivieri D.
      • Berardi N.
      • Maffei L.
      Visual perceptual learning induces long-term potentiation in the visual cortex.
      ), so we currently maintain an open mind on the degree to which plasticity mediating SRP is distributed in V1.
      Figure thumbnail gr5
      Figure 5Molecular mechanisms of SRP. (A) Schematic of a glutamatergic synapse, known molecular players in SRP, and interventional approaches to blocking them. (B) Repeated systemic injections of the NMDAR antagonist 3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) (open symbols) before stimulus exposure prevent mice from undergoing SRP, unlike control saline injections (black symbols), demonstrating a role for the NMDAR in SRP induction. Binocular VEP data are normalized to the amplitude of the Ipsi-only response. (C) Local viral-mediated expression in V1 of a peptide that mimics the cytoplasmic tail of the GluR1 AMPAR subunit (GluR1-CT, open circles) and thereby acts in a dominant-negative fashion to prevent AMPAR insertion, also blocks SRP from developing, whereas a green fluorescent protein (GFP) control infection does not (black circles). This experiment provides evidence both that SRP requires AMPAR insertion for expression and that plasticity within V1 local to the recording site mediates SRP (adapted from [
      • Frenkel M.Y.
      • Sawtell N.B.
      • Diogo A.C.
      • Yoon B.
      • Neve R.L.
      • Bear M.F.
      Instructive effect of visual experience in mouse visual cortex.
      ]). (D) After saturated SRP induction, local delivery of a specific inhibitor peptide (ZIP) of the calcium-dependent protein kinase (PKC) isoform, PKMζ, erases already induced SRP such that familiar (F) (gray circle) and novel (N) stimuli (gray square) evoke VEPs of equivalent basal magnitude where a clear SRP effect had been seen before application (adapted from [
      • Cooke S.F.
      • Bear M.F.
      Visual experience induces long-term potentiation in the primary visual cortex.
      ], with permission from Nature Publishing Group). (E) Mutant mice that do not express the activity-dependent protein Arc/Arg3.1 (open symbols) fail to exhibit SRP. Their wildtype littermates (black symbols) undergo normal SRP. It is, as yet, unclear how Arc/Arg3.1 might impact synaptic potentiation to prevent SRP induction (adapted from [
      • McCurry C.L.
      • Shepherd J.D.
      • Tropea D.
      • Wang K.H.
      • Bear M.F.
      • Sur M.
      Loss of Arc renders the visual cortex impervious to the effects of sensory experience or deprivation.
      ], with permission from Nature Publishing Group). Other abbreviations as in Figure 1, Figure 2, Figure 3.
      Stimulus-specific response potentiation is also prevented by genetic ablation of Arc/Arg 3.1 (
      • McCurry C.L.
      • Shepherd J.D.
      • Tropea D.
      • Wang K.H.
      • Bear M.F.
      • Sur M.
      Loss of Arc renders the visual cortex impervious to the effects of sensory experience or deprivation.
      ) (Figures 5A and 5E). This cytoskeletal-associated protein has been of great interest in the field of memory and synaptic plasticity, because its expression is activity-dependent and driven by both learning (
      • Vazdarjanova A.
      • McNaughton B.L.
      • Barnes C.A.
      • Worley P.F.
      • Guzowski J.F.
      Experience-dependent coincident expression of the effector immediate-early genes arc and Homer 1a in hippocampal and neocortical neuronal networks.
      ) and LTP-inducing stimuli (
      • Steward O.
      • Wallace C.S.
      • Lyford G.L.
      • Worley P.F.
      Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites.
      ). The absence of Arc/Arg3.1 prevents long-term memory and LTP of certain sorts (
      • Plath N.
      • Ohana O.
      • Dammermann B.
      • Errington M.L.
      • Schmitz D.
      • Gross C.
      • et al.
      Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories.
      ,
      • Guzowski J.F.
      • Lyford G.L.
      • Stevenson G.D.
      • Houston F.P.
      • McGaugh J.L.
      • Worley P.F.
      • Barnes C.A.
      Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory.
      ). It is unclear, however, how Arc/Arg3.1 disrupts LTP mechanistically. Arc/Arg3.1 has been shown to play a clear role in the removal of AMPARs from the synaptic membrane (
      • Chowdhury S.
      • Shepherd J.D.
      • Okuno H.
      • Lyford G.
      • Petralia R.S.
      • Plath N.
      • et al.
      Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking.
      ,
      • Shepherd J.D.
      • Rumbaugh G.
      • Wu J.
      • Chowdhury S.
      • Plath N.
      • Kuhl D.
      • et al.
      Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors.
      ), central to the process of long-term depression but of no clear relevance to LTP itself. The mechanistic role that Arc/Arg3.1 plays in SRP is, therefore, yet to be determined.

      Utility of SRP in Psychiatric Research

      Typical neuroleptic drugs, commonly used to treat schizophrenia, target the dopaminergic neurotransmitter system. These substances, such as chlorpromazine and haloperidol, treat positive symptoms but have little impact on cognitive symptoms (
      • Velligan D.I.
      • Miller A.L.
      Cognitive dysfunction in schizophrenia and its importance to outcome: The place of atypical antipsychotics in treatment.
      ). Psychotomimetic substances that impact dopaminergic or serotonergic systems—such as amphetamine or lysergic acid diethylamide, respectively—selectively mimic the positive symptoms of schizophrenia without major cognitive effect (
      • Krystal J.H.
      • Perry Jr, E.B.
      • Gueorguieva R.
      • Belger A.
      • Madonick S.H.
      • Abi-Dargham A.
      • et al.
      Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: Implications for glutamatergic and dopaminergic model psychoses and cognitive function.
      ,
      • Gouzoulis-Mayfrank E.
      • Heekeren K.
      • Neukirch A.
      • Stoll M.
      • Stock C.
      • Obradovic M.
      • Kovar K.A.
      Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): A double-blind, cross-over study in healthy volunteers.
      ). Thus, there is a strong argument that cognitive symptoms do not result from the same imbalance in monoaminergic transmission that is implicated in the positive symptoms. Psychotomimetic NMDAR antagonists such as phencyclidine (PCP) and ketamine do mimic the full range of schizophrenia symptoms, including cognitive symptoms, in normal individuals (
      • Krystal J.H.
      • Karper L.P.
      • Seibyl J.P.
      • Freeman G.K.
      • Delaney R.
      • Bremner J.D.
      • et al.
      Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.
      ) and cause the re-emergence of those symptoms in schizophrenic persons in remission (
      • Lahti A.C.
      • Koffel B.
      • LaPorte D.
      • Tamminga C.A.
      Subanesthetic doses of ketamine stimulate psychosis in schizophrenia.
      ). This observation has given rise to the glutamatergic hypothesis, which asserts that alterations of NMDAR-mediated synaptic transmission/plasticity are causal dysfunctions in schizophrenia (
      • Javitt D.C.
      • Zukin S.R.
      Recent advances in the phencyclidine model of schizophrenia.
      ). Support for this hypothesis comes from mice with reduced NMDAR expression (
      • Mohn A.R.
      • Gainetdinov R.R.
      • Caron M.G.
      • Koller B.H.
      Mice with reduced NMDA receptor expression display behaviors related to schizophrenia.
      ) or function (
      • Ballard T.M.
      • Pauly-Evers M.
      • Higgins G.A.
      • Ouagazzal A.M.
      • Mutel V.
      • Borroni E.
      • et al.
      Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity.
      ), which have behavioral manifestations similar to normal mice under the influence of PCP.
      Cognitive symptoms of schizophrenia include deficits in attention, working memory, and executive function, but there is now also considerable evidence for sensory deficits as assessed, for example, with pre-pulse inhibition (
      • Geyer M.A.
      Are cross-species measures of sensorimotor gating useful for the discovery of procognitive cotreatments for schizophrenia?.
      ). One idea that is gaining support focuses on feed-forward synaptic dysfunction in sensory systems, notably the auditory and visual systems (
      • Javitt D.C.
      When doors of perception close: Bottom-up models of disrupted cognition in schizophrenia.
      ). The NMDAR might play a crucial role in the uniquely nonlinear character of magnocellular responses that allows for an amplification of cortical activity driven by visual stimulation in this pathway (
      • Kwon Y.H.
      • Esguerra M.
      • Sur M.
      NMDA and non-NMDA receptors mediate visual responses of neurons in the cat's lateral geniculate nucleus.
      ,
      • Heggelund P.
      • Hartveit E.
      Neurotransmitter receptors mediating excitatory input to cells in the cat lateral geniculate nucleus I. Lagged cells.
      ,
      • Fox K.
      • Sato H.
      • Daw N.
      The effect of varying stimulus intensity on NMDA-receptor activity in cat visual cortex.
      ), and it has been suggested that this pathway is affected both in schizophrenia (
      • Javitt D.C.
      When doors of perception close: Bottom-up models of disrupted cognition in schizophrenia.
      ,
      • Butler P.D.
      • Silverstein S.M.
      • Dakin S.C.
      Visual perception and its impairment in schizophrenia.
      ) and by psychotomimetic substances (
      • Uhlhaas P.J.
      • Millard I.
      • Muetzelfeldt L.
      • Curran H.V.
      • Morgan C.J.
      Perceptual organization in ketamine users: Preliminary evidence of deficits on night of drug use but not 3 days later.
      ). There are also two other ways in which a reduction of NMDAR function could impact sensation. First, LTP-like plasticity necessary for perceptual learning might be disrupted. Long-term potentiation-like effects, induced noninvasively in the cortex of human subjects with repetitive transcranial magnetic stimulation, are reduced in schizophrenic patients (
      • Frantseva M.V.
      • Fitzgerald P.B.
      • Chen R.
      • Möller B.
      • Daigle M.
      • Daskalakis Z.J.
      Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning.
      ). Also, accompanying articles in this issue of Biological Psychiatry describe deficits in sensory tetanus-induced event-related potential potentiation in schizophrenic subjects (
      • Çavuş I.
      • Reinhart R.M.
      • Roach B.J.
      • Gueorguieva R.
      • Teyler T.J.
      • Clapp W.C.
      • et al.
      Impaired visual cortical plasticity in schizophrenia.
      ,
      • Mears R.P.
      • Spencer K.P.
      Electrophysiological assessment of auditory stimulus-specific plasticity in schizophrenia.
      ). We propose that SRP provides a pre-clinical assay of a related phenomenon that might be understood deeply at the molecular level.
      Second, there is increasing evidence that the schizophrenia-like behavioral disruptions observed in mutant mice with lowered NMDAR function (
      • Mohn A.R.
      • Gainetdinov R.R.
      • Caron M.G.
      • Koller B.H.
      Mice with reduced NMDA receptor expression display behaviors related to schizophrenia.
      ) result primarily from a loss of NMDAR function in parvalbumin-expressing, fast-spiking interneurons (
      • Belforte J.E.
      • Zsiros V.
      • Sklar E.R.
      • Jiang Z.
      • Yu G.
      • Li Y.
      • et al.
      Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes.
      ,
      • Carlén M.
      • Meletis K.
      • Siegle J.H.
      • Cardin J.A.
      • Futai K.
      • Vierling-Claassen D.
      • et al.
      A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior [published online ahead of print April 5].
      ,
      • Korotkova T.
      • Fuchs E.C.
      • Ponomarenko A.
      • von Engelhardt J.
      • Monyer H.
      NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory.
      ). The psychotomimetic actions of noncompetitive NMDAR antagonists such as PCP and ketamine are also believed to arise, in large degree, from blockade of NMDAR expressed in these inhibitory cells (
      • Homayoun H.
      • Moghaddam B.
      NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons.
      ,
      • Behrens M.M.
      • Ali S.S.
      • Dao D.N.
      • Lucero J.
      • Shekhtman G.
      • Quick K.L.
      • Dugan L.L.
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      ). Despite all of the evidence that we have presented in this article revealing that SRP relies upon feedforward Hebbian plasticity in excitatory cells of the cortex, we cannot exclude the possibility that additional mechanisms are involved. Indeed, as we have already discussed, there seems to be some amplification of feedforward Hebbian plasticity in the dramatic enhancement of VEP amplitude as a stimulus becomes familiar during SRP. We have not directly investigated this process, but an obvious hypothesis is that modifications of inhibition act synergistically with plasticity in excitatory cells to discriminate novel and familiar stimuli. At the moment this is pure speculation. Further experiments will be required to establish whether inhibition plays a role in SRP and, if so, whether the process is also NMDAR-dependent.
      Although this review has very clearly made the argument that sensory experience induces plasticity within primary sensory cortex, we would be remiss to ignore the fact that top-down influences mediating attention can also have a major impact on sensory-evoked potentials (
      • Heinze H.J.
      • Luck S.J.
      • Mangun G.R.
      • Hillyard S.A.
      Visual event-related potentials index focused attention within bilateral stimulus arrays I. Evidence for early selection.
      ,
      • Martínez A.
      • Anllo-Vento L.
      • Sereno M.I.
      • Frank L.R.
      • Buxton R.B.
      • Dubowitz D.J.
      • et al.
      Involvement of striate and extrastriate visual cortical areas in spatial attention.
      ). It is known that areas such as prefrontal cortex, in which dysfunction in schizophrenia is well-documented (
      • Volk D.W.
      • Lewis D.A.
      Prefrontal cortical circuits in schizophrenia.
      ), can modulate activity in cortical areas concerned with early visual processing (
      • Noudoost B.
      • Moore T.
      Control of visual cortical signals by prefrontal dopamine.
      ). Moreover, dopamine, a neurotransmitter known to be dysregulated in schizophrenia (
      • Snyder S.H.
      The dopamine hypothesis of schizophrenia: Focus on the dopamine receptor.
      ), can indirectly mediate these top-down effects (
      • Noudoost B.
      • Moore T.
      Control of visual cortical signals by prefrontal dopamine.
      ), even in the absence of major dopaminergic innervation of occipital cortex (
      • Albanese A.
      • Altavista M.C.
      • Rossi P.
      Organization of central nervous system dopaminergic pathways.
      ). For instance, it has been observed that significant abnormalities of VEP latency in schizophrenic subjects (
      • Schwarzkopf S.B.
      • Lamberti J.S.
      • Jiminez M.
      • Kane C.F.
      • Henricks M.
      • Nasrallah H.A.
      Visual evoked potential correlates of positive/negative symptoms in schizophrenia.
      ) are reminiscent of a shortening of VEP latency observed in Parkinsonian subjects after treatment with the dopamine precursor levodopa (
      • Bodis-Wollner I.
      • Yahr M.D.
      • Mylin L.
      • Thornton J.
      Dopaminergic deficiency and delayed visual evoked potentials in humans.
      ). Therefore, we cannot exclude the possibility that, just as with the potential contribution of inhibition discussed in the preceding text, top-down effects mediate some of the transformative effects of repeated visual experience on the VEP and the failure of these effects in schizophrenia due to dopamine dysregulation. Nonetheless, it is clear from the work presented here that plasticity intrinsic to visual cortex is a necessary component for the stimulus-specific potentiation of VEPs through repeated visual presentation.
      Although schizophrenia has been the focus of this article, it is important to note that alterations in visual cortical plasticity have been observed in other psychiatric disorders, such as depression (
      • Normann C.
      • Schmitz D.
      • Fürmaier A.
      • Döing C.
      • Bach M.
      Long-term plasticity of visually evoked potentials in humans is altered in major depression.
      ). Stimulus-specific response potentiation might, therefore, serve as a generalized pre-clinical assay of cortical plasticity. It also seems likely, given the molecular similarities that exist in plasticity across cortical regions, that other sensory modalities could be evaluated in the same fashion. For instance, an auditory tetanus, comprising trains of tone pips, has been shown to potentiate the amplitude of auditory-evoked potentials in humans (
      • Clapp W.C.
      • Kirk I.J.
      • Hamm J.P.
      • Shepherd D.
      • Teyler T.J.
      Induction of LTP in the human auditory cortex by sensory stimulation.
      ), and a report within this issue of Biological Psychiatry reveals reduced plasticity within this modality in schizophrenic subjects (
      • Mears R.P.
      • Spencer K.P.
      Electrophysiological assessment of auditory stimulus-specific plasticity in schizophrenia.
      ). This use of direct sensory stimulation to induce plasticity has a number of advantages over other pre-clinical assays, such as electrically induced LTP: First, it is noninvasive and not obviously aversive. Second, it is relatively naturalistic, and finally, it is beautifully stimulus-specific, allowing for repeated testing across time within the same individual. For these reasons sensory-induced plasticity could provide an assay of normal, dysfunctional, and drug-treated cortical plasticity that is readily translatable from animals to humans.

      Conclusions

      Here we have described the phenomenon of SRP and all of the evidence that strongly implicates it as a manifestation of Hebbian synaptic plasticity. There is still much to be understood about the underlying mechanisms of SRP, and some mystery surrounds its behavioral relevance. We have also yet to determine its generality across species, although similar effects in rats and humans are described in accompanying articles in this issue of Biological Psychiatry. Nevertheless, SRP is a robust and easy-to-assay form of NMDAR-dependent cortical plasticity that occurs in the intact awake mouse. Because it uses the same mechanisms as LTP and shares many properties with sensory perceptual learning, SRP should be valuable for understanding the pathophysiology of cognitive impairment in schizophrenia and for evaluation of potential therapies.
      The primary research discussed in this review article was supported by grant funding from the National Institute of Mental Health , the National Eye Institute , the Howard Hughes Medical Institute , and the Picower Institute Innovations Fund .
      We thank Dr. Idil Çavuş and Dr. Dan Mathalon for their helpful comments on the contents of this article during its preparation.
      Dr. Cooke has no biomedical financial interests or potential conflicts of interest to report. Dr. Bear has a financial interest in Seaside Therapeutics.

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