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1.  Mice with reduced NMDA receptor expression: more consistent with autism than schizophrenia? 
Genes, brain, and behavior  2012;11(6):10.1111/j.1601-183X.2012.00816.x.
Reduced NMDA-receptor (NMDAR) function has been implicated in the pathophysiology of neuropsychiatric disease, most strongly in schizophrenia but also recently in autism spectrum disorders (ASD). To determine the direct contribution of NMDAR dysfunction to disease phenotypes, a mouse model with constitutively reduced expression of the obligatory NR1 subunit has been developed and extensively investigated. Adult NR1neo−/− mice show multiple abnormal behaviors, including reduced social interactions, locomotor hyperactivity, self-injury, deficits in prepulse inhibition, and sensory hypersensitivity, among others. Whereas such phenotypes have largely been interpreted in the context of schizophrenia, these behavioral abnormalities are rather non-specific and are frequently present across models of diseases characterized by negative symptom domains. This study investigated auditory electrophysiological and behavioral paradigms relevant to autism, to determine whether NMDAR hypofunction may be more consistent with adult ASD-like phenotypes. Indeed, transgenic mice demonstrated behavioral deficits relevant to all core ASD symptoms, including decreased social interactions, altered ultrasonic vocalizations, and increased repetitive behaviors. NMDAR disruption recapitulated clinical endophenotypes including reduced prepulse inhibition, auditory-evoked response N1 latency delay, and reduced gamma synchrony. Auditory electrophysiological abnormalities more closely resembled those seen in clinical studies of autism than schizophrenia. These results suggest that NMDA-receptor hypofunction may be associated with a continuum of neuropsychiatric diseases, including schizophrenia and autism. Neural synchrony abnormalities suggest an imbalance of glutamatergic and GABAergic coupling and may provide a target, along with behavioral phenotypes, for preclinical screening of novel therapeutics.
doi:10.1111/j.1601-183X.2012.00816.x
PMCID: PMC3808979  PMID: 22726567
autism; mouse model; NMDA-receptor; behavior; endophenotype
2.  NMDA Receptor Hypofunction, Parvalbumin-Positive Neurons, and Cortical Gamma Oscillations in Schizophrenia 
Schizophrenia Bulletin  2012;38(5):950-957.
Gamma oscillations appear to be dependent on inhibitory neurotransmission from parvalbumin (PV)-containing gamma-amino butyric acid neurons. Thus, the abnormalities in PV neurons found in schizophrenia may underlie the deficits of gamma-band synchrony in the illness. Because gamma-band synchrony is thought to be crucial for cognition, cognitive deficits in schizophrenia may reflect PV neuron dysfunction in cortical neural circuits. Interestingly, it has been suggested that PV alterations in schizophrenia are the consequence of a hypofunction of signaling through N-methyl-D-aspartate (NMDA) receptors (NMDARs). Here, we review recent findings that address the question of how NMDAR hypofunction might produce deficits of PV neuron–mediated inhibition in schizophrenia. We conclude that while dysregulation of NMDARs may play an important role in the pathophysiology of schizophrenia, additional research is required to determine the particular cell type(s) that mediate dysfunctional NMDAR signaling in the illness.
doi:10.1093/schbul/sbs010
PMCID: PMC3446219  PMID: 22355184
glutamate; GABA; inhibition
3.  Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes 
Nature neuroscience  2009;13(1):76-83.
Cortical GABAergic dysfunction may underlie the pathophysiology of psychiatric disorders, including schizophrenia. Here, we characterized a mouse strain in which the essential NR1 subunit of the NMDA receptor (NMDAR) was selectively eliminated in 40–50% of cortical and hippocampal interneurons in early postnatal development. Consistent with the NMDAR hypofunction theory of schizophrenia, distinct schizophrenia-related symptoms emerged after adolescence, including novelty-induced hyperlocomotion, mating and nest-building deficits, as well as anhedonia-like and anxiety-like behaviors. Many of these behaviors were exacerbated by social isolation stress. Social memory, spatial working memory and prepulse inhibition were also impaired. Reduced expression of glutamic acid decarboxylase 67 and parvalbumin was accompanied by disinhibition of cortical excitatory neurons and reduced neuronal synchrony. Postadolescent deletion of NR1 did not result in such abnormalities. These findings suggest that early postnatal inhibition of NMDAR activity in corticolimbic GABAergic interneurons contributes to the pathophysiology of schizophrenia-related disorders.
doi:10.1038/nn.2447
PMCID: PMC2797836  PMID: 19915563
4.  Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioral abnormalities that model symptoms of schizophrenia 
Abnormal function of NMDA receptors is believed to be a contributing factor to the pathophysiology of schizophrenia. NMDAR subunits and postsynaptic interacting proteins of these channels are abnormally expressed in some patients with this illness. In mice, reduced NMDAR expression leads to behaviors analogous to symptoms of schizophrenia, but reports of animals with mutations in core postsynaptic density proteins having similar a phenotype have yet to be reported. Here we show that reduced expression of the neuronal RasGAP and NMDAR-associated protein, SynGAP, results in abnormal behaviors strikingly similar to that reported in mice with reduced NMDAR function. SynGAP mutant mice exhibited non-habituating and persistent hyperactivity that was ameliorated by the antipsychotic clozapine. An NMDAR antagonist, MK-801, induced hyperactivity in normal mice but SynGAP mutants were less responsive, suggesting that NMDAR hypofunction contributes to this behavioral abnormality. SynGAP mutants exhibited enhanced startle reactivity and impaired sensory-motor gating. These mice also displayed a complete lack of social memory and a propensity toward social isolation. Finally, SynGAP mutants had deficits in cued fear conditioning and working memory, indicating abnormal function of circuits that control emotion and choice. Our results demonstrate that SynGAP mutant mice have gross neurological deficits similar to other mouse models of schizophrenia. Because SynGAP interacts with NMDARs, and the signaling activity of this protein is regulated by these channels, our data indicate that SynGAP lies downstream of NMDARs and is a required intermediate for normal neural circuit function and behavior. Taken together, these data support the idea that schizophrenia may arise from abnormal signaling pathways that are mediated by NMDA receptors.
doi:10.1038/npp.2008.223
PMCID: PMC3690772  PMID: 19145222
Schizophrenia; NMDA receptor; postsynaptic density; plasticity; hyperactivity; fear conditioning
5.  Contribution of NMDA Receptor Hypofunction in Prefrontal and Cortical Excitatory Neurons to Schizophrenia-Like Phenotypes 
PLoS ONE  2013;8(4):e61278.
Pharmacological and genetic studies support a role for NMDA receptor (NMDAR) hypofunction in the etiology of schizophrenia. We have previously demonstrated that NMDAR obligatory subunit 1 (GluN1) deletion in corticolimbic interneurons during early postnatal development is sufficient to confer schizophrenia-like phenotypes in mice. However, the consequence of NMDAR hypofunction in cortical excitatory neurons is not well delineated. Here, we characterize a conditional knockout mouse strain (CtxGluN1 KO mice), in which postnatal GluN1 deletion is largely confined to the excitatory neurons in layer II/III of the medial prefrontal cortex and sensory cortices, as evidenced by the lack of GluN1 mRNA expression in in situ hybridization immunocytochemistry as well as the lack of NMDA currents with in vitro recordings. Mutants were impaired in prepulse inhibition of the auditory startle reflex as well as object-based short-term memory. However, they did not exhibit impairments in additional hallmarks of schizophrenia-like phenotypes (e.g. spatial working memory, social behavior, saccharine preference, novelty and amphetamine-induced hyperlocomotion, and anxiety-related behavior). Furthermore, upon administration of the NMDA receptor antagonist, MK-801, there were no differences in locomotor activity versus controls. The mutant mice also showed negligible levels of reactive oxygen species production following chronic social isolation, and recording of miniature-EPSC/IPSCs from layer II/III excitatory neurons in medial prefrontal cortex suggested no alteration in GABAergic activity. All together, the mutant mice displayed cognitive deficits in the absence of additional behavioral or cellular phenotypes reflecting schizophrenia pathophysiology. Thus, NMDAR hypofunction in prefrontal and cortical excitatory neurons may recapitulate only a cognitive aspect of human schizophrenia symptoms.
doi:10.1371/journal.pone.0061278
PMCID: PMC3628715  PMID: 23613827
6.  GABAergic interneuron origin of schizophrenia pathophysiology 
Neuropharmacology  2011;62(3):1574-1583.
Hypofunction of N-methyl-D-aspartic acid-type glutamate receptors (NMDAR) induced by the systemic administration of NMDAR antagonists is well known to cause schizophrenia-like symptoms in otherwise healthy subjects. However, the brain areas or cell types responsible for the emergence of these symptoms following NMDAR hypofunction remain largely unknown. One possibility, the so-called “GABAergic origin hypothesis,” is that NMDAR hypofunction at GABAergic interneurons, in particular, is sufficient for schizophrenia-like effects. In one attempt to address this issue, transgenic mice were generated in which NMDARs were selectively deleted from cortical and hippocampal GABAergic interneurons, a majority of which were parvalbumin (PV)-positive. This manipulation triggered a constellation of phenotypes—from molecular and physiological to behavioral—resembling characteristics of human schizophrenia. Based on these results, and in conjunction with previous literature, we argue that during development, NMDAR hypofunction at cortical, PV-positive, fast-spiking interneurons produces schizophrenia-like effects. This review summarizes the data demonstrating that in schizophrenia, GABAergic (particularly PV-positive) interneurons are disrupted. PV-positive interneurons, many of which display a fast-spiking firing pattern, are critical not only for tight temporal control of cortical inhibition but also for the generation of synchronous membrane-potential gamma-band oscillations. We therefore suggest that in schizophrenia the specific ability of fast-spiking interneurons to control and synchronize disparate cortical circuits is disrupted and that this disruption may underlie many of the schizophrenia symptoms. We further argue that the high vulnerability of corticolimbic fast-spiking interneurons to genetic predispositions and to early environmental insults—including excitotoxicity and oxidative stress—might help to explain their significant contribution to the development of schizophrenia.
doi:10.1016/j.neuropharm.2011.01.022
PMCID: PMC3090452  PMID: 21277876
schizophrenia; fast-spiking interneuron; NMDA receptor hypofunction; parvalbumin; oxidative stress; transgenic mice
7.  A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior 
Molecular Psychiatry  2011;17(5):537-548.
Synchronous recruitment of fast-spiking (FS) parvalbumin (PV) interneurons generates gamma oscillations, rhythms that emerge during performance of cognitive tasks. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists alters gamma rhythms, and can induce cognitive as well as psychosis-like symptoms in humans. The disruption of NMDA receptor (NMDAR) signaling specifically in FS PV interneurons is therefore hypothesized to give rise to neural network dysfunction that could underlie these symptoms. To address the connection between NMDAR activity, FS PV interneurons, gamma oscillations and behavior, we generated mice lacking NMDAR neurotransmission only in PV cells (PV-Cre/NR1f/f mice). Here, we show that mutant mice exhibit enhanced baseline cortical gamma rhythms, impaired gamma rhythm induction after optogenetic drive of PV interneurons and reduced sensitivity to the effects of NMDAR antagonists on gamma oscillations and stereotypies. Mutant mice show largely normal behaviors except for selective cognitive impairments, including deficits in habituation, working memory and associative learning. Our results provide evidence for the critical role of NMDAR in PV interneurons for expression of normal gamma rhythms and specific cognitive behaviors.
doi:10.1038/mp.2011.31
PMCID: PMC3335079  PMID: 21468034
parvalbumin; interneurons; gamma; NMDAR; optogenetics; oscillations
8.  Failure of NMDA receptor hypofunction to induce a pathological reduction in PV-positive GABAergic cell markers 
Neuroscience letters  2010;488(3):267-271.
Reduction in cortical presynaptic markers, notably parvalbumin (PV), for the chandelier subtype of inhibitory γ-amino-butyric acid (GABA) interneurons is a highly replicated post-mortem finding in schizophrenia. Evidence from genetic and pharmacological studies implicates hypofunction of N-methyl-D-aspartate receptor (NMDAR)-mediated glutamatergic signaling as a critical component of the pathophysiology of schizophrenia. Serine racemase (SR) produces the endogenous NMDAR co-agonist D-serine, and disruption of the SR gene results in reduced NMDAR signaling. SR null mutant (−/−) mice were used to study the link between NMDAR hypofunction and decreased PV expression, assessed by immunoreactive (IR) cell density in the medial prefrontal cortex and hippocampus and protein levels in brain homogenates from the frontal cortex and hippocampus. Contrary to expectations, SR −/− mice showed modest elevations in PV-IR cell density and no difference in PV expression in brain homogenate. To control for these surprising results, we investigated PV expression in mice and rats following subchronic phencyclidine or ketamine treatments in adulthood. PV expression was not affected by drug these treatment in either species, failing to reproduce previously published findings. Our findings challenge the hypothesis that pathological deficits in PV expression are simply a consequence of NMDAR hypofunction.
doi:10.1016/j.neulet.2010.11.043
PMCID: PMC3025532  PMID: 21094213
NMDA receptor; D-serine; parvalbumin; GAD67; phencyclidine; ketamine
9.  Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia 
PLoS ONE  2013;8(6):e66327.
It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR) functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of Sp4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. Sp4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67) in both cortex and hippocampus, consistent with abnormal gamma oscillations in Sp4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the Sp4 molecular pathway in Sp4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia.
doi:10.1371/journal.pone.0066327
PMCID: PMC3688895  PMID: 23823008
10.  Glutamate receptor subtypes mediating synaptic activation of prefrontal cortex neurons: relevance for schizophrenia 
Schizophrenia may involve hypofunction of NMDAR-mediated signaling, and alterations in parvalbumin-positive fast-spiking (FS) GABA neurons that may cause abnormal gamma oscillations. It was recently hypothesized that prefrontal cortex (PFC) FS neuron activity is highly dependent on NMDAR activation and that, consequently, FS neuron dysfunction in schizophrenia is secondary to NMDAR hypofunction. However, NMDARs are abundant in synapses onto PFC pyramidal neurons, thus a key question is whether FS neuron or pyramidal cell activation is more dependent on NMDARs. We examined the AMPAR and NMDAR contribution to synaptic activation of FS neurons and pyramidal cells in the PFC of adult mice. In FS neurons, EPSCs had fast decay and weak NMDAR contribution whereas in pyramidal cells EPSCs were significantly prolonged by NMDAR-mediated currents. Moreover, the AMPAR/NMDAR EPSC ratio was higher in FS cells. NMDAR antagonists decreased EPSPs and EPSP-spike coupling more strongly in pyramidal cells than in FS neurons, showing that FS neuron activation is less NMDAR-dependent than pyramidal cell excitation. The precise EPSP-spike coupling produced by fast-decaying EPSCs in FS cells may be important for network mechanisms of gamma oscillations based on feedback inhibition. To test this possibility, we used simulations in a computational network of reciprocally-connected FS neurons and pyramidal cells and found that brief AMPAR-mediated FS neuron activation is crucial to synchronize, via feedback inhibition, pyramidal cells in the gamma frequency band. Our results raise interesting questions about the mechanisms that might link NMDAR hypofunction to alterations of FS neurons in schizophrenia.
doi:10.1523/JNEUROSCI.1970-10.2011
PMCID: PMC3041270  PMID: 21209199
GABA neuron; gamma oscillation; schizophrenia; NMDA receptor; AMPA receptor; cognitive deficit
11.  Altered Excitatory-Inhibitory Balance in the NMDA-Hypofunction Model of Schizophrenia 
Schizophrenia is a common psychiatric disorder of high incidence, affecting approximately 1% of the world population. The essential neurotransmitter pathology of schizophrenia remains poorly defined, despite huge advances over the past half-century in identifying neurochemical and pathological abnormalities in the disease. The dopamine/serotonin hypothesis has originally provided much of the momentum for neurochemical research in schizophrenia. In recent years, the attention has, however, shifted to the glutamate system, the major excitatory neurotransmitter in the CNS and towards a concept of functional imbalance between excitatory and inhibitory transmission at the network level in various brain regions in schizophrenia. The evidence indicating a central role for the NMDA-receptor subtype in the aetiology of schizophrenia has led to the NMDA-hypofunction model of this disease and the use of phencyclidines as a means to induce the NMDA-hypofunction state in animal models. The purpose of this review is to discuss recent findings highlighting the importance of the NMDA-hypofunction model of schizophrenia, both from a clinical perspective, as well as in opening a line of research, which enables electrophysiological studies at the cellular and network level in vitro. In particular, changes in excitation–inhibition (E/I) balance in the NMDA-hypofunction model of the disease and the resulting changes in network behaviours, particularly in gamma frequency oscillatory activity, will be discussed.
doi:10.3389/neuro.02.006.2008
PMCID: PMC2525998  PMID: 18946539
network oscillations; gamma rhythm; phencyclidine; NMDA-hypofunction; interneurons
12.  Brain state-dependent abnormal LFP activity in the auditory cortex of a schizophrenia mouse model 
In schizophrenia, evoked 40-Hz auditory steady-state responses (ASSRs) are impaired, which reflects the sensory deficits in this disorder, and baseline spontaneous oscillatory activity also appears to be abnormal. It has been debated whether the evoked ASSR impairments are due to the possible increase in baseline power. GABAergic interneuron-specific NMDA receptor (NMDAR) hypofunction mutant mice mimic some behavioral and pathophysiological aspects of schizophrenia. To determine the presence and extent of sensory deficits in these mutant mice, we recorded spontaneous local field potential (LFP) activity and its click-train evoked ASSRs from primary auditory cortex of awake, head-restrained mice. Baseline spontaneous LFP power in the pre-stimulus period before application of the first click trains was augmented at a wide range of frequencies. However, when repetitive ASSR stimuli were presented every 20 s, averaged spontaneous LFP power amplitudes during the inter-ASSR stimulus intervals in the mutant mice became indistinguishable from the levels of control mice. Nonetheless, the evoked 40-Hz ASSR power and their phase locking to click trains were robustly impaired in the mutants, although the evoked 20-Hz ASSRs were also somewhat diminished. These results suggested that NMDAR hypofunction in cortical GABAergic neurons confers two brain state-dependent LFP abnormalities in the auditory cortex; (1) a broadband increase in spontaneous LFP power in the absence of external inputs, and (2) a robust deficit in the evoked ASSR power and its phase-locking despite of normal baseline LFP power magnitude during the repetitive auditory stimuli. The “paradoxically” high spontaneous LFP activity of the primary auditory cortex in the absence of external stimuli may possibly contribute to the emergence of schizophrenia-related aberrant auditory perception.
doi:10.3389/fnins.2014.00168
PMCID: PMC4077015  PMID: 25018691
auditory steady-state responses; GABAergic interneurons; gamma oscillation; local field potentials; NMDA receptors; parvalbumin; schizophrenia; mouse models
13.  How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia 
Antioxidants & Redox Signaling  2013;18(12):1444-1462.
Abstract
Significance: Schizophrenia is a complex neuropsychiatric disorder affecting around 1% of the population worldwide. Its mode of inheritance suggests a multigenic neurodevelopmental disorder with symptoms appearing during late adolescence/early adulthood, with its onset strongly influenced by environmental stimuli. Many neurotransmitter systems, including dopamine, glutamate, and gamma-aminobutyric acid, show alterations in affected individuals, and the behavioral and physiological characteristics of the disease can be mimicked by drugs that produce blockade of N-methyl-d-aspartate glutamate receptors (NMDARs). Recent Advances: Mounting evidence suggests that drugs that block NMDARs specifically impair the inhibitory capacity of parvalbumin-expressing (PV+) fast-spiking neurons in adult and developing rodents, and alterations in these inhibitory neurons is one of the most consistent findings in the schizophrenic postmortem brain. Disruption of the inhibitory capacity of PV+ inhibitory neurons will alter the functional balance between excitation and inhibition in prefrontal cortical circuits producing impairment of working memory processes such as those observed in schizophrenia. Critical Issues: Mechanistically, the effect of NMDAR antagonists can be attributed to the activation of the Nox2-dependent reduced form of nicotinamide adenine dinucleotide phosphate oxidase pathway in cortical neurons, which is consistent with the emerging role of oxidative stress in the pathogenesis of mental disorders, specifically schizophrenia. Here we review the mechanisms by which NMDAR antagonists produce lasting impairment of the cortical PV+ neuronal system and the roles played by Nox2-dependent oxidative stress mechanisms. Future Directions: The discovery of the pathways by which oxidative stress leads to unbalanced excitation and inhibition in cortical neural circuits opens a new perspective toward understanding the biological underpinnings of schizophrenia. Antioxid. Redox Signal. 18, 1444–1462.
doi:10.1089/ars.2012.4907
PMCID: PMC3603498  PMID: 22938164
14.  The role of glutamatergic inputs onto parvalbumin-positive interneurons: relevance for schizophrenia 
Reviews in the neurosciences  2012;23(1):97-109.
Cognitive impairment, a core feature of schizophrenia, has been suggested to arise from a disturbance of gamma oscillations that is due to decreased neurotransmission from the parvalbumin (PV) subtype of interneurons. Indeed, PV interneurons have uniquely fast membrane and synaptic properties that are crucially important for network functions such as feedforward inhibition or gamma oscillations. The causes leading to impairment of PV neurotransmission in schizophrenia are still under investigation. Interestingly, NMDA receptors (NMDARs) antagonism results in schizophrenia-like symptoms in healthy adults. Additionally, systemic NMDAR antagonist administration increases prefrontal cortex pyramidal cell firing, apparently by producing disinhibition, and repeated exposure to NMDA antagonists leads to changes in the GABAergic markers that mimic the impairments found in schizophrenia. Based on these findings, PV neuron deficits in schizophrenia have been proposed to be secondary to (NMDAR) hypofunction at glutamatergic synapses onto these cells. However, NMDARs generate long-lasting postsynaptic currents that result in prolonged depolarization of the postsynaptic cells, a property inconsistent with the role of PV cells in network dynamics. Here, we review evidence leading to the conclusion that cortical disinhibition and GABAergic impairment produced by NMDAR antagonists are unlikely to be mediated viaNMDARs at glutamatergic synapses onto mature cortical PV neurons.
doi:10.1515/revneuro-2011-0059
PMCID: PMC3607105  PMID: 22718616
cognition; GABA; NMDA; oscillations
15.  Knockout of NMDA Receptors in Parvalbumin Interneurons Recreates Autism-Like Phenotypes 
Autism is a disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors with few effective treatments. New evidence suggests that autism has reliable electrophysiological endophenotypes and that these measures may be caused by n-methyl-d-aspartic acid receptor (NMDAR) disruption on parvalbumin (PV)-containing interneurons. These findings could be used to create new translational biomarkers. Recent developments have allowed for cell-type selective knockout of NMDARs in order to examine the perturbations caused by disrupting specific circuits. This study examines several electrophysiological and behavioral measures disrupted in autism using a PV-selective reduction in NMDA R1 subunit. Mouse electroencephalograph (EEG) was recorded in response to auditory stimuli. Event-related potential (ERP) component amplitude and latency analysis, social testing, and premating ultrasonic vocalizations (USVs) recordings were performed. Correlations were examined between the ERP latency and behavioral measures. The N1 ERP latency was delayed, sociability was reduced, and mating USVs were impaired in PV-selective NMDA Receptor 1 Knockout (NR1 KO) as compared with wild-type mice. There was a significant correlation between N1 latency and sociability but not between N1 latency and premating USV power or T-maze performance. The increases in N1 latency, impaired sociability, and reduced vocalizations in PV-selective NR1 KO mice mimic similar changes found in autism. Electrophysiological changes correlate to reduced sociability, indicating that the local circuit mechanisms controlling N1 latency may be utilized in social function. Therefore, we propose that behavioral and electrophysiological alterations in PV-selective NR1 KO mice may serve as a useful model for therapeutic development in autism.
doi:10.1002/aur.1264
PMCID: PMC4064157  PMID: 23441094
autism; electrophysiology; endophenotype; animal models; NMDA receptor 1 knockout
16.  Disruption of social approach by MK-801, amphetamine, and fluoxetine in adolescent C57BL/6J mice 
Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10 mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice.
doi:10.1016/j.ntt.2012.07.007
PMCID: PMC3509253  PMID: 22898204
amphetamine; autism; ethanol withdrawal; repetitive behavior; social approach; stereotypy
17.  Mice Lacking NMDA Receptors in Parvalbumin Neurons Display Normal Depression-Related Behavior and Response to Antidepressant Action of NMDAR Antagonists 
PLoS ONE  2014;9(1):e83879.
The underlying circuit imbalance in major depression remains unknown and current therapies remain inadequate for a large group of patients. Discovery of the rapid antidepressant effects of ketamine - an NMDA receptor (NMDAR) antagonist – has linked the glutamatergic system to depression. Interestingly, dysfunction in the inhibitory GABAergic system has also been proposed to underlie depression and deficits linked to GABAergic neurons have been found with human imaging and in post-mortem material from depressed patients. Parvalbumin-expressing (PV) GABAergic interneurons regulate local circuit function through perisomatic inhibition and their activity is NMDAR-dependent, providing a possible link between NMDAR and the inhibitory system in the antidepressant effect of ketamine. We have therefore investigated the role of the NMDAR-dependent activity of PV interneurons for the development of depression-like behavior as well as for the response to rapid antidepressant effects of NMDAR antagonists. We used mutant mice lacking NMDA neurotransmission specifically in PV neurons (PV-Cre+/NR1f/f) and analyzed depression-like behavior and anhedonia. To study the acute and sustained effects of a single NMDAR antagonist administration, we established a behavioral paradigm of repeated exposure to forced swimming test (FST). We did not observe altered behavioral responses in the repeated FST or in a sucrose preference test in mutant mice. In addition, the behavioral response to administration of NMDAR antagonists was not significantly altered in mutant PV-Cre+/NR1f/f mice. Our results show that NMDA-dependent neurotransmission in PV neurons is not necessary to regulate depression-like behaviors, and in addition that NMDARs on PV neurons are not a direct target for the NMDAR-induced antidepressant effects of ketamine and MK801.
doi:10.1371/journal.pone.0083879
PMCID: PMC3894182  PMID: 24454710
18.  Involvement of NR2A- or NR2B-containing N-methyl-D-aspartate receptors in the potentiation of cortical layer 5 pyramidal neurone inputs depends on the developmental stage 
In the cortex, NMDA receptors (NMDARs) play a critical role in the control of synaptic plasticity processes. We have previously shown in rat visual cortex that the application of a high frequency of stimulation (HFS) protocol used to induce long-term potentiation (LTP) in layer 2/3 leads to a parallel potentiation of excitatory and inhibitory inputs received by cortical layer 5 pyramidal neurons without changing the excitation/inhibition (E/I) balance of the pyramidal neuron, indicating a homeostatic control of this parameter.
We show here that the blockade of NMDARs of the neuronal network prevents the potentiation of excitatory and inhibitory inputs and this result opens to question the role of the NMDAR isoform involved in the induction of LTP, actually being strongly debated. In P18-P23 rat cortical slices, the blockade of synaptic NR2B-containing NMDARs prevents the induction of the potentiation induced by the HFS protocol, whereas the blockade of NR2A-containing NMDARs reduced the potentiation itself. In P29-P32 cortical slices, the specific activation of NR2A-containing receptors fully ensures the potentiation of excitatory and inhibitory inputs. These results constitute the first report of a functional shift in subunit composition of NMDARs during the critical period (P12-P36) which explains the relative contribution of both NR2B- and NR2A-containing NMDARs in synaptic plasticity processes. These effects of HFS protocol are mediated by the activation of synaptic NMDARs but our results also indicate that the homeostatic control of the E/I balance is independent of NMDARs activation and is due to specialized recurrent interactions between excitatory and inhibitory networks.
doi:10.1111/j.1460-9568.2007.05671.x
PMCID: PMC2533738  PMID: 17650107
2-Amino-5-phosphonovalerate; pharmacology; Animals; Cerebral Cortex; cytology; growth & development; physiology; Electric Stimulation; Electrophysiology; Neuronal Plasticity; physiology; Patch-Clamp Techniques; Pyramidal Cells; drug effects; physiology; Rats; Receptors; N-Methyl-D-Aspartate; drug effects; physiology; Synapses; physiology; Visual Cortex; cytology; growth & development; physiology
19.  Shank3 Deficiency Induces NMDA Receptor Hypofunction via an Actin-Dependent Mechanism 
The Journal of Neuroscience  2013;33(40):15767-15778.
Shank3, which encodes a scaffolding protein at glutamatergic synapses, is a genetic risk factor for autism. In this study, we examined the impact of Shank3 deficiency on the NMDA-type glutamate receptor, a key player in cognition and mental illnesses. We found that knockdown of Shank3 with a small interfering RNA (siRNA) caused a significant reduction of NMDAR-mediated ionic or synaptic current, as well as the surface expression of NR1 subunits, in rat cortical cultures. The effect of Shank3 siRNA on NMDAR currents was blocked by an actin stabilizer, and was occluded by an actin destabilizer, suggesting the involvement of actin cytoskeleton. Since actin dynamics is regulated by the GTPase Rac1 and downstream effector p21-activated kinase (PAK), we further examined Shank3 regulation of NMDARs when Rac1 or PAK was manipulated. We found that the reducing effect of Shank3 siRNA on NMDAR currents was mimicked and occluded by specific inhibitors for Rac1 or PAK, and was blocked by constitutively active Rac1 or PAK. Immunocytochemical data showed a strong reduction of F-actin clusters after Shank3 knockdown, which was occluded by a PAK inhibitor. Inhibiting cofilin, the primary downstream target of PAK and a major actin depolymerizing factor, prevented Shank3 siRNA from reducing NMDAR currents and F-actin clusters. Together, these results suggest that Shank3 deficiency induces NMDAR hypofunction by interfering with the Rac1/PAK/cofilin/actin signaling, leading to the loss of NMDAR membrane delivery or stability. It provides a potential mechanism for the role of Shank3 in cognitive deficit in autism.
doi:10.1523/JNEUROSCI.1175-13.2013
PMCID: PMC3787498  PMID: 24089484
20.  Differential Regulation of GABAB Receptor Trafficking by Different Modes of N-methyl-d-aspartate (NMDA) Receptor Signaling* 
The Journal of Biological Chemistry  2014;289(10):6681-6694.
Background: Heterodimerization of GABAB1 and GABAB2 subunits is required for functional GABABRs.
Results: GABABR subunits are differentially regulated by activation of synaptic or extrasynaptic NMDARs.
Conclusion: GABABR trafficking and function is regulated by NMDARs.
Significance: GABABRs are potential targets for treating diseases such as stroke and cerebral ischemia.
Inhibitory GABAB receptors (GABABRs) can down-regulate most excitatory synapses in the CNS by reducing postsynaptic excitability. Functional GABABRs are heterodimers of GABAB1 and GABAB2 subunits and here we show that the trafficking and surface expression of GABABRs is differentially regulated by synaptic or pathophysiological activation of NMDA receptors (NMDARs). Activation of synaptic NMDARs using a chemLTP protocol increases GABABR recycling and surface expression. In contrast, excitotoxic global activation of synaptic and extrasynaptic NMDARs by bath application of NMDA causes the loss of surface GABABRs. Intriguingly, exposing neurons to extreme metabolic stress using oxygen/glucose deprivation (OGD) increases GABAB1 but decreases GABAB2 surface expression. The increase in surface GABAB1 involves enhanced recycling and is blocked by the NMDAR antagonist AP5. The decrease in surface GABAB2 is also blocked by AP5 and by inhibiting degradation pathways. These results indicate that NMDAR activity is critical in GABABR trafficking and function and that the individual subunits can be separately controlled to regulate neuronal responsiveness and survival.
doi:10.1074/jbc.M113.487348
PMCID: PMC3945329  PMID: 24425870
G Protein-coupled Receptors (GPCR); GABA Receptors; Glutamate Receptor Ionotropic (AMPA, NMDA); Neurodegeneration; Neurotransmitter Receptors; Receptor Endocytosis; Receptor Recycling; GABAB Receptor; Chem-LTP; Oxygen-glucose Deprivation (OGD)
21.  Activation of 5-HT2A/C Receptors Counteracts 5-HT1A Regulation of N-Methyl-D-aspartate Receptor Channels in Pyramidal Neurons of Prefrontal Cortex* 
The Journal of Biological Chemistry  2008;283(25):17194-17204.
Abnormal serotonin-glutamate interaction in prefrontal cortex (PFC) is implicated in the pathophysiology of many mental disorders, including schizophrenia and depression. However, the mechanisms by which this interaction occurs remain unclear. Our previous study has shown that activation of 5-HT1A receptors inhibits N-methyl-d-aspartate (NMDA) receptor (NMDAR) currents in PFC pyramidal neurons by disrupting microtubule-based transport of NMDARs. Here we found that activation of 5-HT2A/C receptors significantly attenuated the effect of 5-HT1A on NMDAR currents and microtubule depolymerization. The counteractive effect of 5-HT2A/C on 5-HT1A regulation of synaptic NMDAR response was also observed in PFC pyramidal neurons from intact animals treated with various 5-HT-related drugs. Moreover, 5-HT2A/C stimulation triggered the activation of extracellular signal-regulated kinase (ERK) in dendritic processes. Inhibition of the β-arrestin/Src/dynamin signaling blocked 5-HT2A/C activation of ERK and the counteractive effect of 5-HT2A/C on 5-HT1A regulation of NMDAR currents. Immunocytochemical studies showed that 5-HT2A/C treatment blocked the inhibitory effect of 5-HT1A on surface NR2B clusters on dendrites, which was prevented by cellular knockdown of β-arrestins. Taken together, our study suggests that serotonin, via 5-HT1A and 5-HT2A/C receptor activation, regulates NMDAR functions in PFC neurons in a counteractive manner. 5-HT2A/C, by activating ERK via the β-arrestin-dependent pathway, opposes the 5-HT1A disruption of microtubule stability and NMDAR transport. These findings provide a framework for understanding the complex interactions between serotonin and NMDARs in PFC, which could be important for cognitive and emotional control in which both systems are highly involved.
doi:10.1074/jbc.M801713200
PMCID: PMC2427346  PMID: 18442977
22.  Baseline gamma power during auditory steady-state stimulation in schizophrenia 
Several studies have reported deficits in γ oscillatory activity elicited by sensory stimulation or cognitive processes in schizophrenia patients (SZ) compared to healthy control subjects (HC). However, the evidence for cortical hyperexcitability and reduced function of N-methyl-D-aspartate receptors (NMDARs) on parvalbumin-expressing inhibitory interneurons in schizophrenia leads to the prediction that γ activity should rather be increased in SZ, but data supporting this hypothesis have been lacking. One possibility is that baseline induced γ power is increased, an effect that might have gone unnoticed in studies of stimulus-locked oscillations. Here we addressed this question by re-analyzing the data from a previously published study on the 40 Hz auditory steady-state response (ASSR) in schizophrenia in which dipole source localization was used to examine γ responses in the left and right auditory cortices. Subjects were 16 HC and 18 chronic SZ, who listened to trains of clicks presented at 40 Hz during electroencephalogram recording. Independent component analysis was used to remove ocular artifacts. Power spectra were computed for the pre-stimulus baseline period. We found that baseline power was higher in SZ than HC at 40 Hz in the left auditory cortex. Baseline 40 Hz power in the left auditory cortex was also correlated with ASSR evoked power in SZ. Thus, γ oscillation abnormalities in schizophrenia may include abnormal increases in baseline power as well as deficits in evoked oscillations. These baseline increases could be the sign of NMDAR hypofunction on parvalbumin-expressing inhibitory interneurons, which would be consistent with acute NMDAR antagonism and genetic ablation models of schizophrenia.
doi:10.3389/fnhum.2011.00190
PMCID: PMC3267371  PMID: 22319485
schizophrenia; gamma oscillation; auditory steady-state response; NMDA receptor
23.  Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology 
Genes, Brain, and Behavior  2010;10(2):210-222.
There is substantial evidence implicating N-methyl-d-aspartate receptors (NMDARs) in memory and cognition. It has also been suggested that NMDAR hypofunction might underlie the cognitive deficits observed in schizophrenia since morphological changes, including alterations in the dendritic architecture of pyramidal neurons in the prefrontal cortex (PFC), have been reported in the schizophrenic brain post mortem. Here, we used a genetic model of NMDAR hypofunction, a serine racemase knockout (SR−/−) mouse in which the first coding exon of the mouse serine racemase gene has been deleted, to explore the role of d-serine in regulating cognitive functions as well as dendritic architecture. SR −/− mice exhibited a significantly disrupted representation of the order of events in distinct experiences as revealed by object recognition and odor sequence tests; however, SR −/− animals were unimpaired in the detection of novel objects and in spatial displacement, and showed intact relational memory in a test of transitive inference. In addition, SR −/− mice exhibited normal sociability and preference for social novelty. Neurons in the medial PFC of SR−/− mice displayed reductions in the complexity, total length, and spine density of apical dendrites. These findings demonstrate that d-serine is important for specific aspects of cognition, as well as in regulating dendritic morphology of pyramidal neurons in the mPFC. Moreover, they suggest that NMDAR hypofunction might, in part, be responsible for the cognitive deficits and synaptic changes associated with schizophrenia, and highlight this signaling pathway as a potential target for therapeutic intervention.
doi:10.1111/j.1601-183X.2010.00656.x
PMCID: PMC3348622  PMID: 21029376
D-serine; NMDA receptors; dendritic morphology; temporal order memory; sequence memory; schizophrenia
24.  Social Isolation Exacerbates Schizophrenia-like Phenotypes via Oxidative Stress in Cortical Interneurons 
Biological psychiatry  2013;73(10):1024-1034.
Background
Our previous studies indicated that NMDA receptor (NMDAR) deletion from a subset of corticolimbic interneurons in the mouse brain during early postnatal development is sufficient to trigger several behavioral and pathophysiological features resembling the symptoms of human schizophrenia. Interestingly, many of these behavioral phenotypes are exacerbated by social isolation stress. However, the mechanisms underlying the exacerbating effects of social isolation are unclear.
Methods
Using GABAergic interneuron-specific NMDAR hypofunction mouse model (Ppp1r2-cre/fGluN1 KO mice), we investigated whether oxidative stress is implicated in the social isolation-induced exacerbation of schizophrenia-like phenotypes and further explored the underlying mechanism of elevated oxidative stress in KO mice.
Results
The reactive oxygen species (ROS) level in the cortex of group-housed KO mice was normal at eight weeks although increased at 16 weeks old. Post-weaning social isolation (PWSI) augmented the ROS levels in KO mice at both ages, which was accompanied by the onset of behavioral phenotype. Chronic treatment with apocynin, an ROS scavenger, abolished markers of oxidative stress and partially alleviated schizophrenia-like behavioral phenotypes in KO mice. Markers of oxidative stress following PWSI were especially prominent in cortical parvalbumin (PV)-positive interneurons. The vulnerability of PV interneurons to oxidative stress was associated with down-regulation of peroxisome proliferator-activated receptor α coactivator-13 (PGC-1α), a master regulator of mitochondrial energy metabolism and antioxidation.
Conclusions
These results suggest that a PWSI-mediated impairment in antioxidant defense mechanisms, presumably mediated by PGC-1α downregulation in the NMDAR-deleted PV-positive interneurons, results in oxidative stress, which, in turn, may contribute to exacerbation of schizophrenia-like behavioral phenotypes.
doi:10.1016/j.biopsych.2012.12.004
PMCID: PMC3638045  PMID: 23348010
interneuron; NMDA receptor hypofunction; oxidative stress; parvalbumin; PGC-1α; schizophrenia; social isolation; transgenic mice
25.  NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia 
Schizophrenia is a disabling mental illness that is now recognized as a neurodevelopmental disorder. It is likely that genetic risk factors interact with environmental perturbations to affect normal brain development and that this altered trajectory results in a combination of positive, negative, and cognitive symptoms. Although the exact pathophysiology of schizophrenia is unknown, the N-methyl-D-aspartate receptor (NMDAR), a major glutamate receptor subtype, has received great attention. Proper expression and regulation of NMDARs in the brain is critical for learning and memory processes as well as cortical plasticity and maturation. Evidence from both animal models and human studies implicates a dysfunction of NMDARs both in disease progression and symptoms of schizophrenia. Furthermore, mutations in many of the known genetic risk factors for schizophrenia suggest that NMDAR hypofunction is a convergence point for schizophrenia. In this review, we discuss how disrupted NMDAR function leads to altered neurodevelopment that may contribute to the progression and development of symptoms for schizophrenia, particularly cognitive deficits. We review the shared signaling pathways among the schizophrenia susceptibility genes DISC1, neuregulin1, and dysbindin, focusing on the AKT/GSK3β pathway, and how their mutations and interactions can lead to NMDAR dysfunction during development. Additionally, we explore what open questions remain and suggest where schizophrenia research needs to move in order to provide mechanistic insight into the cause of NMDAR dysfunction, as well as generate possible new avenues for therapeutic intervention.
doi:10.3389/fncel.2013.00031
PMCID: PMC3608949  PMID: 23543703
gene; NMDA receptors; psychiatric disorders; neurodevelopment; schizophrenia

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