Abstract
Background
NMDA receptor (NMDAR) hypofunction has been implicated in several psychiatric disorders
with impairment of cognitive flexibility. However, the molecular mechanism of how
NMDAR hypofunction with decreased NMDAR tone causes the impairment of cognitive flexibility
has been minimally understood. Furthermore, it has been unclear whether hippocampal
astrocytes regulate NMDAR tone and cognitive flexibility.
Methods
We employed cell type–specific genetic manipulations, ex vivo electrophysiological
recordings, sniffer patch recordings, cutting-edge biosensor for norepinephrine, and
behavioral assays to investigate whether astrocytes can regulate NMDAR tone by releasing
D-serine and glutamate. Subsequently, we further investigated the role of NMDAR tone
in heterosynaptic long-term depression, metaplasticity, and cognitive flexibility.
Results
We found that hippocampal astrocytes regulate NMDAR tone via BEST1-mediated corelease
of D-serine and glutamate. Best1 knockout mice exhibited reduced NMDAR tone and impairments of homosynaptic and α1 adrenergic receptor–dependent heterosynaptic long-term depression, which leads to
defects in metaplasticity and cognitive flexibility. These impairments in Best1 knockout mice can be rescued by hippocampal astrocyte-specific BEST1 expression or
enhanced NMDAR tone through D-serine supplement. D-serine injection in Best1 knockout mice during initial learning rescues subsequent reversal learning.
Conclusions
These findings indicate that NMDAR tone during initial learning is important for subsequent
learning, and hippocampal NMDAR tone regulated by astrocytic BEST1 is critical for
heterosynaptic long-term depression, metaplasticity, and cognitive flexibility.
Keywords
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References
- Spatial memory and cognitive flexibility trade-offs: To be or not to be flexible, that is the question.Anim Behav. 2019; 147: 129-136
- Reduced behavioral flexibility in autism spectrum disorders.Neuropsychology. 2013; 27: 152-160
- Cognitive impairment of executive function as a core symptom of schizophrenia.World J Biol Psychiatry. 2009; 10: 442-451
- Mental flexibility impairment in drivers with early Alzheimer’s disease: A simulator-based study.IATSS Res. 2013; 37: 16-20
- Executive functions in Alzheimer disease: A systematic review.Front Aging Neurosci. 2019; 10: 437
- NMDAR hypofunction animal models of schizophrenia.Front Mol Neurosci. 2019; 12: 185
- Mice with reduced NMDA receptor expression: More consistent with autism than schizophrenia?.Genes Brain Behav. 2012; 11: 740-750
- NMDA neurotransmission dysfunction in behavioral and psychological symptoms of Alzheimer’s disease.Curr Neuropharmacol. 2012; 10: 272-285
- Transgenic mice lacking NMDAR-dependent LTD exhibit deficits in behavioral flexibility.Neuron. 2008; 58: 104-117
- Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior.Proc Natl Acad Sci U S A. 2015; 112: E6964-E6972
- Parallel loss of hippocampal LTD and cognitive flexibility in a genetic model of hyperdopaminergia.Neuropsychopharmacology. 2007; 32: 2108-2116
- D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning.Neuropsychopharmacology. 2008; 33: 1004-1018
- The neural basis of reversal learning: An updated perspective.Neuroscience. 2017; 345: 12-26
- Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade.Proc Natl Acad Sci U S A. 1992; 89: 4363-4367
- Enhanced long-term depression and impaired reversal learning in phosphodiesterase 4B-knockout (PDE4B−/−) mice.Neuropharmacology. 2011; 61: 138-147
- Mice overexpressing type 1 adenylyl cyclase show enhanced spatial memory flexibility in the absence of intact synaptic long-term depression.Learn Mem. 2013; 20: 352-357
- Bell-shaped D-serine actions on hippocampal long-term depression and spatial memory retrieval.Cereb Cortex. 2008; 18: 2391-2401
- Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice.Learn Mem. 2008; 16: 28-37
- Astroglial versus neuronal D-serine: Fact checking.Trends Neurosci. 2017; 40: 517-520
- Astroglial versus neuronal D-serine: Check your controls.Trends Neurosci. 2017; 40: 520-522
- An autocrine purinergic signaling controls astrocyte-induced neuronal excitation.Sci Rep. 2017; 7: 11280
- Astrocytic p38α MAPK drives NMDA receptor-dependent long-term depression and modulates long-term memory.Nat Commun. 2019; 10: 2968
- Distribution and function of the bestrophin-1 (Best1) channel in the brain.Exp Neurobiol. 2017; 26: 113-121
- TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation.Cell. 2012; 151: 25-40
- High glutamate permeability and distal localization of Best1 channel in CA1 hippocampal astrocyte.Mol Brain. 2013; 6: 54
- Adrenergic calcium signaling in astrocyte networks within the hippocampal slice.J Neurosci. 1995; 15: 5535-5550
- Novel form of long-term synaptic depression in rat hippocampus induced by activation of alpha 1 adrenergic receptors.J Neurophysiol. 2004; 91: 1071-1077
- NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus.Neuron. 1998; 21: 1151-1162
- Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer’s disease.Brain. 2017; 140: 3023-3038
- Impairments in remote memory caused by the lack of type 2 IP3 receptors.Glia. 2019; 67: 1976-1989
- Heterosynaptic long-term depression mediated by ATP released from astrocytes.Glia. 2013; 61: 178-191
- Heterosynaptic plasticity prevents runaway synaptic dynamics.J Neurosci. 2013; 33: 15915-15929
- Metaplasticity: The plasticity of synaptic plasticity.Trends Neurosci. 1996; 19: 126-130
- Mechanisms of heterosynaptic metaplasticity.Philos Trans R Soc Lond B Biol Sci. 2013; 369: 20130148
- Astrocytes control sensory acuity via tonic inhibition in the thalamus.Neuron. 2020; 108: 691-706.e10
- Astrocytic control of synaptic NMDA receptors.J Physiol. 2007; 581: 1057-1081
- Chronic stress alters spatial representation and bursting patterns of place cells in behaving mice.Sci Rep. 2015; 5: 16235
- What do we know about gliotransmitter release from astrocytes?.Philos Trans R Soc Lond B Biol Sci. 2014; 369: 20130592
- Making sense of astrocytic calcium signals—From acquisition to interpretation.Nat Rev Neurosci. 2020; 21: 551-564
- The tripartite glutamatergic synapse.Neuropharmacology. 2021; 199: 108758
- Tonic activation of NMDA receptors by ambient glutamate of non-synaptic origin in the rat hippocampus.J Physiol. 2007; 580: 373-383
- The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1).J Gen Physiol. 2006; 127: 577-589
- Channel-mediated astrocytic glutamate modulates hippocampal synaptic plasticity by activating postsynaptic NMDA receptors [published correction appears in Mol Brain 2021; 14:103].Mol Brain. 2015; 8: 7
- Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists.Cell. 2012; 150: 633-646
- Modulation of dopamine and noradrenaline release and of intracellular Ca2+ concentration by presynaptic glutamate receptors in hippocampus.Br J Pharmacol. 1994; 113: 1439-1447
- Glutamate-stimulated release of norepinephrine in hippocampal slices of animal models of attention-deficit/hyperactivity disorder (spontaneously hypertensive rat) and depression/anxiety-like behaviours (Wistar-Kyoto rat).Brain Res. 2008; 1200: 107-115
- A genetically encoded fluorescent sensor for rapid and specific in vivo detection of norepinephrine.Neuron. 2019; 102: 745-761.e8
- Heterosynaptic long-term depression in the hippocampus.J Physiol Paris. 1996; 90: 165-166
- Bidirectional long-term modification of synaptic effectiveness in the adult and immature hippocampus.J Neurosci. 1993; 13: 2910-2918
- Loss of IP3 receptor-dependent Ca2+ increases in hippocampal astrocytes does not affect baseline CA1 pyramidal neuron synaptic activity.J Neurosci. 2008; 28: 4967-4973
- Inositol 1,4,5-trisphosphate receptor type 2-independent Ca 2+ release from the endoplasmic reticulum in astrocytes.Glia. 2019; 67: 113-124
- TRPA1 channels are regulators of astrocyte basal calcium levels and long-term potentiation via constitutive D-serine release.J Neurosci. 2013; 33: 10143-10153
- Ca 2+ transients in astrocyte fine processes occur via Ca 2+ influx in the adult mouse hippocampus.Glia. 2016; 64: 2093-2103
- Ultrasonic neuromodulation via astrocytic TRPA1 [published correction appears in Curr Biol 2020; 30:948.Curr Biol. 2019; 29: 3386-3401.e8
- Cell selective conditional null mutations of serine racemase demonstrate a predominate localization in cortical glutamatergic neurons.Cell Mol Neurobiol. 2012; 32: 613-624
- Asc-1 transporter regulation of synaptic activity via the tonic release of d-serine in the forebrain.Cereb Cortex. 2017; 27: 1573-1587
- Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness.Neuron. 2017; 94: 840-854.e7
- Long-term potentiation depends on release of D-serine from astrocytes.Nature. 2010; 463: 232-236
- Neuronal D-serine and glycine release via the Asc-1 transporter regulates NMDA receptor-dependent synaptic activity.J Neurosci. 2013; 33: 3533-3544
- Synaptic plasticity: Multiple forms, functions, and mechanisms.Neuropsychopharmacology. 2008; 33: 18-41
- Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression.Proc Natl Acad Sci U S A. 2013; 110: 4027-4032
- The cystine-glutamate exchanger (xCT, Slc7a11) is expressed in significant concentrations in a subpopulation of astrocytes in the mouse brain.Glia. 2018; 66: 951-970
- SNARE protein-dependent glutamate release from astrocytes.J Neurosci. 2000; 20: 666-673
- Tweety-homolog (Ttyh) family encodes the pore-forming subunits of the swelling-dependent volume-regulated anion channel (VRACswell) in the brain.Exp Neurobiol. 2019; 28: 183-215
- Glutamate-releasing SWELL1 channel in astrocytes modulates synaptic transmission and promotes brain damage in stroke.Neuron. 2019; 102: 813-827.e6
- Synergy between vesicular and non-vesicular gliotransmission regulates synaptic plasticity and working memory.bioRxiv. 2021; https://doi.org/10.1101/2021.03.25.437028
- Tonic NMDA receptor-mediated current in prefrontal cortical pyramidal cells and fast-spiking interneurons.J Neurophysiol. 2012; 107: 2232-2243
- Pharmacological heterogeneity of release-regulating presynaptic AMPA/kainate receptors in the rat brain: Study with receptor antagonists.Neurochem Int. 2003; 42: 283-292
- Locus ceruleus norepinephrine release: A central regulator of CNS spatio-temporal activation?.Front Synaptic Neurosci. 2016; 8: 25
- Hypothesis for the local control of norepinephrine release.in: Usdin E. Kopin I.J. Barchas J. Catecholamines: Basic and Clinical Frontiers, Proceedings of the Fourth International Catecholamine Symposium, Pacific Grove, California, September 17-22, 1978. Pergamon, New York1979: 1792-1794
- GABAergic network activation of glial cells underlies hippocampal heterosynaptic depression.J Neurosci. 2006; 26: 5370-5382
- Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains.J Neurosci. 2002; 22: 183-192
- PI3Kγ is required for NMDA receptor-dependent long-term depression and behavioral flexibility.Nat Neurosci. 2011; 14: 1447-1454
- Hippocampal long-term depression mediates spatial reversal learning in the Morris water maze.Neuropharmacology. 2013; 64: 65-73
- Impairment of contextual conditioned fear extinction after microinjection of alpha-1-adrenergic blocker prazosin into the medial prefrontal cortex.Behav Brain Res. 2010; 211: 89-95
- Prazosin during threat discrimination boosts memory of the safe stimulus.Learn Mem. 2017; 24: 597-601
- Wisconsin Card Sorting Test performance in healthy, older adults: Relationship to age, sex, education, and IQ.J Clin Psychol. 1993; 49: 54-60
- The decline of glutamate-stimulated norepinephrine release in aging rat brain.FASEB J. 2019; 33 (501.511–501.511)
- The mechanistic link between selective vulnerability of the locus coeruleus and neurodegeneration in Alzheimer’s disease.Acta Neuropathol. 2021; 141: 631-650
Article Info
Publication History
Published online: October 20, 2021
Accepted:
October 8,
2021
Received in revised form:
October 7,
2021
Received:
May 20,
2021
Identification
Copyright
© 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.