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 #
5R01MH085666-09
Application #
9271087
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Nadler, Laurie S
Project Start
2009-04-01
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
9
Fiscal Year
2017
Total Cost
$383,844
Indirect Cost
$133,844
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19102
Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun (2016) GSK3β Hyperactivity during an Early Critical Period Impairs Prefrontal Synaptic Plasticity and Induces Lasting Deficits in Spine Morphology and Working Memory. Neuropsychopharmacology 41:3003-3015
Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun (2016) Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex. Brain Res 1641:217-33
Li, Meng-Lin; Hu, Xi-Quan; Li, Feng et al. (2015) Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end? Prog Neuropsychopharmacol Biol Psychiatry 60:66-76
Li, Meng-Lin; Yang, Sha-Sha; Xing, Bo et al. (2015) LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment. Exp Neurol 273:190-201
Monaco, Sarah A; Gulchina, Yelena; Gao, Wen-Jun (2015) NR2B subunit in the prefrontal cortex: A double-edged sword for working memory function and psychiatric disorders. Neurosci Biobehav Rev 56:127-38
Urban, Kimberly R; Gao, Wen-Jun (2015) Evolution of the Study of Methylphenidate and Its Actions on the Adult Versus Juvenile Brain. J Atten Disord 19:603-19
Urban, Kimberly R; Gao, Wen-Jun (2014) Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootropic drugs in the healthy developing brain. Front Syst Neurosci 8:38
Chandler, Daniel J; Waterhouse, Barry D; Gao, Wen-Jun (2014) New perspectives on catecholaminergic regulation of executive circuits: evidence for independent modulation of prefrontal functions by midbrain dopaminergic and noradrenergic neurons. Front Neural Circuits 8:53
Pitcher, Jonathan; Abt, Anna; Myers, Jaclyn et al. (2014) Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction. J Clin Invest 124:656-69
Ferguson, Brielle R; Gao, Wen-Jun (2014) Development of thalamocortical connections between the mediodorsal thalamus and the prefrontal cortex and its implication in cognition. Front Hum Neurosci 8:1027

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