The role of NMDAR in the pathophysiological process of schizophrenia Abstract Schizophrenia (SZ) is increasingly recognized as a neurodevelopmental disorder with cognitive impairments often preceding the onset of psychosis, while the N-methyl-D-aspartate receptor (NMDAR) has long been associated with learning and memory processes, neurodevelopment, and SZ. Yet, the cause of the cognitive deficits and what initiates the pathological process are incompletely understood. Given the importance of NMDARs for cognitive functions, it is likely that NMDAR mis-regulation/dysfunction plays a critical role in the pathological process of SZ. In the past two decades, a remarkably convergent observation across several animal models of SZ and human postmortem studies is the phenomenon of NMDAR hypofunction. However, the vast majority of SZ- related research has focused on NMDAR function in adults, leaving the role of NMDARs during brain development unexplored. An important next step is to identify the mechanisms that cause NMDAR dysfunction with different insults during development. To address this issue, we have conducted some pilot studies. Our preliminary data indicated that along with working memory and learning deficits, protein levels of NMDAR subunits are significantly reduced in the prefrontal cortex and hippocampus, starting from the juvenile period and becoming more prominent during the adolescent period. Furthermore, there is a clear alteration in NMDAR-mediated current in the prefrontal neurons in both methylazoxymethanol (MAM)-exposed rat and DISC1 mutant mouse models during the early stage of development. Based on these observations, we hypothesize that NMDAR hypofunction begins in the early stage of postnatal development and progresses until adulthood. This process is universal to different animal models. Correcting NMDAR hypofunction in the early stage (juvenile period) would be effective to restore glutamatergic synaptic transmission and thus to rescue cognitive deficits. Using a combination of molecular, biochemical, and physiological techniques, along with behavioral tests, in Aim 1 we will determine the time course of NMDAR mis-expression and dysfunction in the prefrontal cortex and hippocampus during postnatal development;as well as testing learning and memory functions in both MAM-exposed rats and inducible DISC1 mutant mice.
In Aim 2 we will investigate the mechanisms underlying NMDAR dysfunction during postnatal development, focusing on transcriptional repression by epigenetic remodeling and signaling pathways involved in NMDAR downregulation.
In Aim 3 we will determine whether pharmacologically correcting NMDAR hypofunction in the early stage (juvenile period) of development is able to restore NMDAR functions and thus rescue learning and memory deficits in MAM-exposed rats and DISC1 mutant mice. We believe that these experiments will elucidate the progression of NMDAR hypofunction, provide mechanistic insight into its cause, and generate possible new avenues for therapeutic intervention. Furthermore, the results would provide an interesting platform for exploring how early NMDAR hypofunction contributes to cognitive deficits in SZ and will address the very important conceptual question of whether early stage treatment is able to prevent the progression or reverse the cognitive deficits associated with this disease.

Public Health Relevance

The goal of this project is to study when and how NMDARs, a major receptor type in excitatory synaptic transmission in the brain, are downregulated in the prefrontal cortex and hippocampus during early development in methylazoxymethanol (MAM)-exposed rats and DISC1 mutant mice. We will simultaneously investigate whether pharmacologically correcting NMDAR hypofunction in the early stage (juvenile period) of development is able to restore cognitive function in animal models for schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH085666-06A1
Application #
8761553
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Nadler, Laurie S
Project Start
2009-04-01
Project End
2019-05-31
Budget Start
2014-08-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Coley, Austin A; Gao, Wen-Jun (2018) PSD95: A synaptic protein implicated in schizophrenia or autism? Prog Neuropsychopharmacol Biol Psychiatry 82:187-194
Xing, Bo; Han, Genie; Wang, Min-Juan et al. (2018) Juvenile treatment with mGluR2/3 agonist prevents schizophrenia-like phenotypes in adult by acting through GSK3?. Neuropharmacology 137:359-371
Ferguson, Brielle R; Gao, Wen-Jun (2018) PV Interneurons: Critical Regulators of E/I Balance for Prefrontal Cortex-Dependent Behavior and Psychiatric Disorders. Front Neural Circuits 12:37
Zhang, Yu-Xiang; Akumuo, Rita C; EspaƱa, Rodrigo A et al. (2018) The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory. Neuropharmacology 141:113-125
Ferguson, Brielle R; Gao, Wen-Jun (2018) Thalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex. Biol Psychiatry 83:657-669
Li, Meng-Lin; Gulchina, Yelena; Monaco, Sarah A et al. (2017) Juvenile treatment with a novel mGluR2 agonist/mGluR3 antagonist compound, LY395756, reverses learning deficits and cognitive flexibility impairments in adults in a neurodevelopmental model of schizophrenia. Neurobiol Learn Mem 140:52-61
Urban, Kimberly R; Li, Yan-Chun; Xing, Bo et al. (2017) A Clinically-Relevant Dose of Methylphenidate Enhances Synaptic Inhibition in the Juvenile Rat Prefrontal Cortex. J Reward Defic Syndr Addict Sci 2:69-77
Gulchina, Yelena; Xu, Song-Jun; Snyder, Melissa A et al. (2017) Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia. J Neurochem 143:320-333
Urban, Kimberly R; Gao, Wen-Jun (2017) Psychostimulants As Cognitive Enhancers in Adolescents: More Risk than Reward? Front Public Health 5:260
Li, Yan-Chun; Yang, Sha-Sha; Gao, Wen-Jun (2016) Disruption of Akt signaling decreases dopamine sensitivity in modulation of inhibitory synaptic transmission in rat prefrontal cortex. Neuropharmacology 108:403-14

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