Advertisement

Reduced Glutamate Decarboxylase 65 Protein Within Primary Auditory Cortex Inhibitory Boutons in Schizophrenia

  • Caitlin E. Moyer
    Affiliations
    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Kristen M. Delevich
    Affiliations
    Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Kenneth N. Fish
    Affiliations
    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Josephine K. Asafu-Adjei
    Affiliations
    Department of Statistics, University of Pittsburgh, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Allan R. Sampson
    Affiliations
    Department of Statistics, University of Pittsburgh, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Karl-Anton Dorph-Petersen
    Affiliations
    Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania

    Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark

    Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University, Aarhus, Denmark
    Search for articles by this author
  • David A. Lewis
    Affiliations
    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Robert A. Sweet
    Correspondence
    Address correspondence to Robert A. Sweet, M.D., Western Psychiatric Institute and Clinic, Department of Psychiatry, Biomedical Science Tower, Room W1645, 3811 O'Hara Street, Pittsburgh, PA 15213-2593
    Affiliations
    Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania

    Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
    Search for articles by this author

      Background

      Schizophrenia is associated with perceptual and physiological auditory processing impairments that may result from primary auditory cortex excitatory and inhibitory circuit pathology. High-frequency oscillations are important for auditory function and are often reported to be disrupted in schizophrenia. These oscillations may, in part, depend on upregulation of gamma-aminobutyric acid synthesis by glutamate decarboxylase 65 (GAD65) in response to high interneuron firing rates. It is not known whether levels of GAD65 protein or GAD65-expressing boutons are altered in schizophrenia.

      Methods

      We studied two cohorts of subjects with schizophrenia and matched control subjects, comprising 27 pairs of subjects. Relative fluorescence intensity, density, volume, and number of GAD65-immunoreactive boutons in primary auditory cortex were measured using quantitative confocal microscopy and stereologic sampling methods. Bouton fluorescence intensities were used to compare the relative expression of GAD65 protein within boutons between diagnostic groups. Additionally, we assessed the correlation between previously measured dendritic spine densities and GAD65-immunoreactive bouton fluorescence intensities.

      Results

      GAD65-immunoreactive bouton fluorescence intensity was reduced by 40% in subjects with schizophrenia and was correlated with previously measured reduced spine density. The reduction was greater in subjects who were not living independently at time of death. In contrast, GAD65-immunoreactive bouton density and number were not altered in deep layer 3 of primary auditory cortex of subjects with schizophrenia.

      Conclusions

      Decreased expression of GAD65 protein within inhibitory boutons could contribute to auditory impairments in schizophrenia. The correlated reductions in dendritic spines and GAD65 protein suggest a relationship between inhibitory and excitatory synapse pathology in primary auditory cortex.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • McCarley R.W.
        • Faux S.F.
        • Shenton M.E.
        • Nestor P.G.
        • Adams J.
        Event-related potentials in schizophrenia: Their biological and clinical correlates and a new model of schizophrenic pathophysiology.
        Schizophr Res. 1991; 4: 209-231
        • Leitman D.I.
        • Sehatpour P.
        • Higgins B.A.
        • Foxe J.J.
        • Silipo G.
        • Javitt D.C.
        Sensory deficits and distributed hierarchical dysfunction in schizophrenia.
        Am J Psychiatry. 2010; 167: 818-827
        • Javitt D.C.
        • Shelley A.
        • Ritter W.
        Associated deficits in mismatch negativity generation and tone matching in schizophrenia.
        Clin Neurophysiol. 2000; 111: 1733-1737
        • Javitt D.C.
        • Steinschneider M.
        • Schroeder C.E.
        • Vaughan Jr, H.G.
        • Arezzo J.C.
        Detection of stimulus deviance within primate primary auditory cortex: Intracortical mechanisms of mismatch negativity (MMN) generation.
        Brain Res. 1994; 667: 192-200
        • Naatanen R.
        • Kahkonen S.
        Central auditory dysfunction in schizophrenia as revealed by the mismatch negativity (MMN) and its magnetic equivalent MMNm: A review.
        Int J Neuropsychopharmacol. 2009; 12: 125-135
        • Javitt D.C.
        When doors of perception close: Bottom-up models of disrupted cognition in schizophrenia.
        Annu Rev Clin Psychol. 2009; 5: 249-275
        • Kasai K.
        • Nakagome K.
        • Itoh K.
        • Koshida I.
        • Hata A.
        • Iwanami A.
        • et al.
        Impaired cortical network for preattentive detection of change in speech sounds in schizophrenia: A high-resolution event-related potential study.
        Am J Psychiatry. 2002; 159: 546-553
        • Rabinowicz E.F.
        • Silipo G.
        • Goldman R.
        • Javitt D.C.
        Auditory sensory dysfunction in schizophrenia.
        Arch Gen Psychiatry. 2000; 57: 1149-1155
        • Leitman D.I.
        • Foxe J.J.
        • Butler P.D.
        • Saperstein A.
        • Revheim N.
        • Javitt D.C.
        Sensory contributions to impaired prosodic processing in schizophrenia.
        Biol Psychiatry. 2005; 58: 56-61
        • Shea T.L.
        • Sergejew A.A.
        • Burnham D.
        • Jones C.
        • Rossell S.L.
        • Copolov D.L.
        • Egan G.F.
        Emotional prosodic processing in auditory hallucinations.
        Schizophr Res. 2007; 90: 214-220
        • Leitman D.I.
        • Ziwich R.
        • Pasternak R.
        • Javitt D.C.
        Theory of Mind (ToM) and counterfactuality deficits in schizophrenia: Misperception or misinterpretation?.
        Psychol Med. 2006; 36: 1075-1083
        • Heffner H.E.
        • Heffner R.S.
        Hearing loss in Japanese macaques following bilateral auditory cortex lesions.
        J Neurophysiol. 1986; 55: 256-271
        • Rybalko N.
        • Suta D.
        • Nwabueze-Ogbo F.
        • Syka J.
        Effect of auditory cortex lesions on the discrimination of frequency-modulated tones in rats.
        Eur J Neurosci. 2006; 23: 1614-1622
        • McCarley R.W.
        • Wible C.G.
        • Frumin M.
        • Hirayasu Y.
        • Levitt J.J.
        • Fischer I.A.
        • Shenton M.E.
        MRI anatomy of schizophrenia.
        Biol Psychiatry. 1999; 45: 1099-1119
        • Rajarethinam R.
        • Sahni S.
        • Rosenberg D.R.
        • Keshavan M.S.
        Reduced superior temporal gyrus volume in young offspring of patients with schizophrenia.
        Am J Psychiatry. 2004; 161: 1121-1124
        • Hirayasu Y.
        • McCarley R.W.
        • Salisbury D.F.
        • Tanaka S.
        • Kwon J.S.
        • Frumin M.
        • et al.
        Planum temporale and Heschl gyrus volume reduction in schizophrenia: A magnetic resonance imaging study of first-episode patients.
        Arch Gen Psychiatry. 2000; 57: 692-699
        • Kasai K.
        • Shenton M.E.
        • Salisbury D.F.
        • Hirayasu Y.
        • Onitsuka T.
        • Spencer M.H.
        • et al.
        Progressive decrease of left Heschl gyrus and planum temporale gray matter volume in first-episode schizophrenia: A longitudinal magnetic resonance imaging study.
        Arch Gen Psychiatry. 2003; 60: 766-775
        • Salisbury D.F.
        • Kuroki N.
        • Kasai K.
        • Shenton M.E.
        • McCarley R.W.
        Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia.
        Arch Gen Psychiatry. 2007; 64: 521-529
        • Takahashi T.
        • Wood S.J.
        • Yung A.R.
        • Soulsby B.
        • McGorry P.D.
        • Suzuki M.
        • et al.
        Progressive gray matter reduction of the superior temporal gyrus during transition to psychosis.
        Arch Gen Psychiatry. 2009; 66: 366-376
        • Jeschke M.
        • Lenz D.
        • Budinger E.
        • Herrmann C.S.
        • Ohl F.W.
        Gamma oscillations in gerbil auditory cortex during a target-discrimination task reflect matches with short-term memory.
        Brain Res. 2008; 1220: 70-80
        • Pastor M.A.
        • Artieda J.
        • Arbizu J.
        • Marti-Climent J.M.
        • Penuelas I.
        • Masdeu J.C.
        Activation of human cerebral and cerebellar cortex by auditory stimulation at 40 Hz.
        J Neurosci. 2002; 22: 10501-10506
        • Picton T.W.
        • John M.S.
        • Dimitrijevic A.
        • Purcell D.
        Human auditory steady-state responses.
        Int J Audiol. 2003; 42: 177-219
        • Brenner C.A.
        • Sporns O.
        • Lysaker P.H.
        • O'Donnell B.F.
        EEG synchronization to modulated auditory tones in schizophrenia, schizoaffective disorder, and schizotypal personality disorder.
        Am J Psychiatry. 2003; 160: 2238-2240
        • Krishnan G.P.
        • Hetrick W.P.
        • Brenner C.A.
        • Shekhar A.
        • Steffen A.N.
        • O'Donnell B.F.
        Steady state and induced auditory gamma deficits in schizophrenia.
        Neuroimage. 2009; 47: 1711-1719
        • Kwon J.S.
        • O'Donnell B.F.
        • Wallenstein G.V.
        • Greene R.W.
        • Hirayasu Y.
        • Nestor P.G.
        • et al.
        Gamma frequency-range abnormalities to auditory stimulation in schizophrenia.
        Arch Gen Psychiatry. 1999; 56: 1001-1005
        • Light G.A.
        • Hsu J.L.
        • Hsieh M.H.
        • Meyer-Gomes K.
        • Sprock J.
        • Swerdlow N.R.
        • Braff D.L.
        Gamma band oscillations reveal neural network cortical coherence dysfunction in schizophrenia patients.
        Biol Psychiatry. 2006; 60: 1231-1240
        • Spencer K.M.
        • Salisbury D.F.
        • Shenton M.E.
        • McCarley R.W.
        Gamma-band auditory steady-state responses are impaired in first episode psychosis.
        Biol Psychiatry. 2008; 64: 369-375
        • Brenner C.A.
        • Krishnan G.P.
        • Vohs J.L.
        • Ahn W.Y.
        • Hetrick W.P.
        • Morzorati S.L.
        • O'Donnell B.F.
        Steady state responses: Electrophysiological assessment of sensory function in schizophrenia.
        Schizophr Bull. 2009; 35: 1065-1077
        • Hamm J.P.
        • Gilmore C.S.
        • Picchetti N.A.
        • Sponheim S.R.
        • Clementz B.A.
        Abnormalities of neuronal oscillations and temporal integration to low- and high-frequency auditory stimulation in schizophrenia.
        Biol Psychiatry. 2011; 69: 989-996
        • Lenz D.
        • Jeschke M.
        • Schadow J.
        • Naue N.
        • Ohl F.W.
        • Herrmann C.S.
        Human EEG very high frequency oscillations reflect the number of matches with a template in auditory short-term memory.
        Brain Res. 2008; 1220: 81-92
        • Cobb S.R.
        • Buhl E.H.
        • Halasy K.
        • Paulsen O.
        • Somogyi P.
        Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons.
        Nature. 1995; 378: 75-78
        • Uhlhaas P.J.
        • Singer W.
        Abnormal neural oscillations and synchrony in schizophrenia.
        Nat Rev Neurosci. 2010; 11: 100-113
        • Atallah B.V.
        • Scanziani M.
        Instantaneous modulation of gamma oscillation frequency by balancing excitation with inhibition.
        Neuron. 2009; 62: 566-577
        • Patel A.B.
        • de Graaf R.A.
        • Martin D.L.
        • Battaglioli G.
        • Behar K.L.
        Evidence that GAD65 mediates increased GABA synthesis during intense neuronal activity in vivo.
        J Neurochem. 2006; 97: 385-396
        • Martin D.L.
        • Martin S.B.
        • Wu S.J.
        • Espina N.
        Regulatory properties of brain glutamate decarboxylase (GAD): The apoenzyme of GAD is present principally as the smaller of two molecular forms of GAD in brain.
        J Neurosci. 1991; 11: 2725-2731
        • Tian N.
        • Petersen C.
        • Kash S.
        • Baekkeskov S.
        • Copenhagen D.
        • Nicoll R.
        The role of the synthetic enzyme GAD65 in the control of neuronal gamma-aminobutyric acid release.
        Proc Natl Acad Sci U S A. 1999; 96: 12911-12916
        • Gonzalez-Burgos G.
        • Lewis D.A.
        GABA neurons and the mechanisms of network oscillations: Implications for understanding cortical dysfunction in schizophrenia.
        Schizophr Bull. 2008; 34: 944-961
        • Kaur S.
        • Rose H.J.
        • Lazar R.
        • Liang K.
        • Metherate R.
        Spectral integration in primary auditory cortex: Laminar processing of afferent input, in vivo and in vitro.
        Neuroscience. 2005; 134: 1033-1045
        • Liu B.H.
        • Wu G.K.
        • Arbuckle R.
        • Tao H.W.
        • Zhang L.I.
        Defining cortical frequency tuning with recurrent excitatory circuitry.
        Nat Neurosci. 2007; 10: 1594-1600
        • Javitt D.C.
        • Steinschneider M.
        • Schroeder C.E.
        • Arezzo J.C.
        Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: Implications for schizophrenia.
        Proc Natl Acad Sci U S A. 1996; 93: 11962-11967
        • Dorph-Petersen K.A.
        • Delevich K.M.
        • Marcsisin M.J.
        • Zhang W.
        • Sampson A.R.
        • Gundersen H.J.
        • et al.
        Pyramidal neuron number in layer 3 of primary auditory cortex of subjects with schizophrenia.
        Brain Res. 2009; 1285: 42-57
        • Sweet R.A.
        • Bergen S.E.
        • Sun Z.
        • Sampson A.R.
        • Pierri J.N.
        • Lewis D.A.
        Pyramidal cell size reduction in schizophrenia: Evidence for involvement of auditory feedforward circuits.
        Biol Psychiatry. 2004; 55: 1128-1137
        • Sweet R.A.
        • Bergen S.E.
        • Sun Z.
        • Marcsisin M.J.
        • Sampson A.R.
        • Lewis D.A.
        Anatomical evidence of impaired feedforward auditory processing in schizophrenia.
        Biol Psychiatry. 2007; 61: 854-864
        • Sweet R.A.
        • Henteleff R.A.
        • Zhang W.
        • Sampson A.R.
        • Lewis D.A.
        Reduced dendritic spine density in auditory cortex of subjects with schizophrenia.
        Neuropsychopharmacology. 2009; 34: 374-389
        • Wehr M.
        • Zador A.M.
        Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex.
        Nature. 2003; 426: 442-446
        • Wu G.K.
        • Arbuckle R.
        • Liu B.H.
        • Tao H.W.
        • Zhang L.I.
        Lateral sharpening of cortical frequency tuning by approximately balanced inhibition.
        Neuron. 2008; 58: 132-143
        • Fish K.N.
        • Sweet R.A.
        • Deo A.J.
        • Lewis D.A.
        An automated segmentation methodology for quantifying immunoreactive puncta number and fluorescence intensity in tissue sections.
        Brain Res. 2008; 1240: 62-72
        • Dracheva S.
        • Elhakem S.L.
        • McGurk S.R.
        • Davis K.L.
        • Haroutunian V.
        GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions of elderly patients with schizophrenia.
        J Neurosci Res. 2004; 76: 581-592
        • Guidotti A.
        • Auta J.
        • Davis J.M.
        • Giorgi-Gerevini V.
        • Dwivedi Y.
        • Grayson D.R.
        • et al.
        Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: A postmortem brain study.
        Arch Gen Psychiatry. 2000; 57: 1061-1069
        • Impagnatiello F.
        • Guidotti A.R.
        • Pesold C.
        • Dwivedi Y.
        • Caruncho H.
        • Pisu M.G.
        • et al.
        A decrease of reelin expression as a putative vulnerability factor in schizophrenia.
        Proc Natl Acad Sci U S A. 1998; 95: 15718-15723
        • Curley A.A.
        • Arion D.
        • Volk D.W.
        • Asafu-Adjei J.K.
        • Sampson A.R.
        • Fish K.N.
        • Lewis D.A.
        Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: Clinical, protein, and cell type-specific features.
        Am J Psychiatry. 2011; 168: 921-929
        • Benes F.M.
        • Todtenkopf M.S.
        • Logiotatos P.
        • Williams M.
        Glutamate decarboxylase(65)-immunoreactive terminals in cingulate and prefrontal cortices of schizophrenic and bipolar brain.
        J Chem Neuroanat. 2000; 20: 259-269
        • Braendgaard H.
        • Gundersen H.J.
        The impact of recent stereological advances on quantitative studies of the nervous system.
        J Neurosci Methods. 1986; 18: 39-78
        • Chen J.
        • Mizushige T.
        • Nishimune H.
        Active zone density is conserved during synaptic growth but impaired in aged mice.
        J Comp Neurol. 2011; 520: 434-452
        • Ruiz R.
        • Cano R.
        • Casanas J.J.
        • Gaffield M.A.
        • Betz W.J.
        • Tabares L.
        Active zones and the readily releasable pool of synaptic vesicles at the neuromuscular junction of the mouse.
        J Neurosci. 2011; 31: 2000-2008
        • Rasser P.E.
        • Schall U.
        • Todd J.
        • Michie P.T.
        • Ward P.B.
        • Johnston P.
        • et al.
        Gray matter deficits, mismatch negativity, and outcomes in schizophrenia.
        Schizophr Bull. 2011; 37: 131-140
        • Mathews J.R.
        • Barch D.M.
        Emotion responsivity, social cognition, and functional outcome in schizophrenia.
        J Abnorm Psychol. 2010; 119: 50-59
        • Chang Y.C.
        • Gottlieb D.I.
        Characterization of the proteins purified with monoclonal antibodies to glutamic acid decarboxylase.
        J Neurosci. 1988; 8: 2123-2130
        • Asada H.
        • Kawamura Y.
        • Maruyama K.
        • Kume H.
        • Ding R.
        • Ji F.Y.
        • et al.
        Mice lacking the 65 kDa isoform of glutamic acid decarboxylase (GAD65) maintain normal levels of GAD67 and GABA in their brains but are susceptible to seizures.
        Biochem Biophys Res Commun. 1996; 229: 891-895
        • Choi S.Y.
        • Morales B.
        • Lee H.K.
        • Kirkwood A.
        Absence of long-term depression in the visual cortex of glutamic acid decarboxylase-65 knock-out mice.
        J Neurosci. 2002; 22: 5271-5276
        • Kash S.F.
        • Tecott L.H.
        • Hodge C.
        • Baekkeskov S.
        Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase.
        Proc Natl Acad Sci U S A. 1999; 96: 1698-1703
        • Fish K.N.
        • Sweet R.A.
        • Lewis D.A.
        Differential distribution of proteins regulating GABA synthesis and reuptake in axon boutons of subpopulations of cortical interneurons.
        Cereb Cortex. 2011; 21: 2450-2460
        • Hajos M.
        • Hoffmann W.E.
        • Kocsis B.
        Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillation: relevance to schizophrenia.
        Biol Psychiatry. 2008; 63: 1075-1083
        • Edwards C.R.
        • Skosnik P.D.
        • Steinmetz A.B.
        • O'Donnell B.F.
        • Hetrick W.P.
        Sensory gating impairments in heavy cannabis users are associated with altered neural oscillations.
        Behav Neurosci. 2009; 123: 894-904
        • Markram H.
        • Toledo-Rodriguez M.
        • Wang Y.
        • Gupta A.
        • Silberberg G.
        • Wu C.
        Interneurons of the neocortical inhibitory system.
        Nat Rev Neurosci. 2004; 5: 793-807
        • Cardin J.A.
        • Carlen M.
        • Meletis K.
        • Knoblich U.
        • Zhang F.
        • Deisseroth K.
        • et al.
        Driving fast-spiking cells induces gamma rhythm and controls sensory responses.
        Nature. 2009; 459: 663-667
        • Sohal V.S.
        • Zhang F.
        • Yizhar O.
        • Deisseroth K.
        Parvalbumin neurons and gamma rhythms enhance cortical circuit performance.
        Nature. 2009; 459: 698-702
        • Chen Q.C.
        • Jen P.H.
        Bicuculline application affects discharge patterns, rate-intensity functions, and frequency tuning characteristics of bat auditory cortical neurons.
        Hear Res. 2000; 150: 161-174
        • Wang J.
        • Caspary D.
        • Salvi R.J.
        GABA-A antagonist causes dramatic expansion of tuning in primary auditory cortex.
        Neuroreport. 2000; 11: 1137-1140
        • Wang J.
        • McFadden S.L.
        • Caspary D.
        • Salvi R.
        Gamma-aminobutyric acid circuits shape response properties of auditory cortex neurons.
        Brain Res. 2002; 944: 219-231
        • Mann E.O.
        • Mody I.
        Control of hippocampal gamma oscillation frequency by tonic inhibition and excitation of interneurons.
        Nat Neurosci. 2010; 13: 205-212
        • Edden R.A.
        • Muthukumaraswamy S.D.
        • Freeman T.C.
        • Singh K.D.
        Orientation discrimination performance is predicted by GABA concentration and gamma oscillation frequency in human primary visual cortex.
        J Neurosci. 2009; 29: 15721-15726
        • Choe B.Y.
        • Kim K.T.
        • Suh T.S.
        • Lee C.
        • Paik I.H.
        • Bahk Y.W.
        • et al.
        1H magnetic resonance spectroscopy characterization of neuronal dysfunction in drug-naïve, chronic schizophrenia.
        Acad Radiol. 1994; 1: 211-216
        • Stanley J.A.
        • Drost D.J.
        • Williamson P.C.
        • Carr T.J.
        In vivo proton MRS study of glutamate and schizophrenia.
        in: Nasrallah H.A. Pettegrew J.W. NMR Spectroscopy in Psychiatric Brain Disorders. American Psychiatric Press, Washington, DC1995: 21-44
        • Yoon J.H.
        • Maddock R.J.
        • Rokem A.
        • Silver M.A.
        • Minzenberg M.J.
        • Ragland J.D.
        • Carter C.S.
        Gamma-aminobutyric acid concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression.
        J Neurosci. 2010; 30: 3777-3781
        • Lewis D.A.
        • Sweet R.A.
        Schizophrenia from a neural circuitry perspective: Advancing toward rational pharmacological therapies.
        J Clin Invest. 2009; 119: 706-716
        • Fung S.J.
        • Webster M.J.
        • Sivagnanasundaram S.
        • Duncan C.
        • Elashoff M.
        • Weickert C.S.
        Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia.
        Am J Psychiatry. 2010; 167: 1479-1488
        • Hashimoto T.
        • Bazmi H.H.
        • Mirnics K.
        • Wu Q.
        • Sampson A.R.
        • Lewis D.A.
        Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia.
        Am J Psychiatry. 2008; 165: 479-489
        • Lewis D.A.
        • Hashimoto T.
        • Volk D.W.
        Cortical inhibitory neurons and schizophrenia.
        Nat Rev Neurosci. 2005; 6: 312-324
        • Fung S.J.
        • Webster M.J.
        • Weickert C.S.
        Expression of VGluT1 and VGAT mRNAs in human dorsolateral prefrontal cortex during development and in schizophrenia.
        Brain Res. 2011; 1388: 22-31
        • Mataga N.
        • Mizuguchi Y.
        • Hensch T.K.
        Experience-dependent pruning of dendritic spines in visual cortex by tissue plasminogen activator.
        Neuron. 2004; 44: 1031-1041
        • Murphy D.D.
        • Cole N.B.
        • Greenberger V.
        • Segal M.
        Estradiol increases dendritic spine density by reducing GABA neurotransmission in hippocampal neurons.
        J Neurosci. 1998; 18: 2550-2559
        • Hendry S.H.
        • Jones E.G.
        Activity-dependent regulation of GABA expression in the visual cortex of adult monkeys.
        Neuron. 1988; 1: 701-712
        • Patz S.
        • Wirth M.J.
        • Gorba T.
        • Klostermann O.
        • Wahle P.
        Neuronal activity and neurotrophic factors regulate GAD-65/67 mRNA and protein expression in organotypic cultures of rat visual cortex.
        Eur J Neurosci. 2003; 18: 1-12
        • Welker E.
        • Soriano E.
        • Van der L.H.
        Plasticity in the barrel cortex of the adult mouse: Effects of peripheral deprivation on GAD-immunoreactivity.
        Exp Brain Res. 1989; 74: 441-452
        • Hartman K.N.
        • Pal S.K.
        • Burrone J.
        • Murthy V.N.
        Activity-dependent regulation of inhibitory synaptic transmission in hippocampal neurons.
        Nat Neurosci. 2006; 9: 642-649
        • Huttenlocher P.R.
        Synaptic density in human frontal cortex–developmental changes and effects of aging.
        Brain Res. 1979; 163: 195-205
        • Rakic P.
        • Bourgeois J.P.
        • Eckenhoff M.F.
        • Zecevic N.
        • Goldman-Rakic P.S.
        Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex.
        Science. 1986; 232: 232-235
        • Cahill M.E.
        • Xie Z.
        • Day M.
        • Photowala H.
        • Barbolina M.V.
        • Miller C.A.
        • et al.
        Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes.
        Proc Natl Acad Sci U S A. 2009; 106: 13058-13063
        • Gundersen H.J.
        The smooth fractionator.
        J Microsc. 2002; 207: 191-210