Schizophrenia is a chronic, debilitating mental disorder characterized by positive symptoms (psychosis), negative symptoms (apathy) and cognitive impairments as well as physiologic abnormalities such as hypofontality, disrupted eye tracking and abnormal cortical event related potentials. The syndromic features can best be replicated in normal volunteers by the administration of subanaesthetic doses of dissociative anaesthetics, which are non-competitive inhibitors of the NMDA receptor. Based on post-mortem findings, we proposed 15 years ago that cortical NMDA receptor hypofunction was a core pathophysiologic feature of schizophrenia, accounting for the enduring and disabling negative and cognitive symptoms whereas psychosis was down-stream complication of this primary cortical pathology. During the last period of support, we have shown with a mouse genetic model for the reduced availability of the NMDA receptor co- agonist, D-serine, in schizophrenia that these mice exhibit reduced dendritic complexity and fewer dendritic spines, neuronal pathology most likely responsible for negative symptoms and cognitive impairments in schizophrenia. In the proposed studies, we will resolve a controversy over the cellular localization of serine racemase (SR), which synthesizes D-serine, by exploiting cell specific expression of Cre to inactivate SR in neurons or astrocytes. Using these mutants, we will determine how synaptic D-serine is regulated during glutamatergic neurotransmission. We will then determine how D-serine deficiency affects dendritic maturation and spine formation, when in development and what is the gene expression signature of this effect. This expression profile will be compared to that found in the cortex in schizophrenia and in other mouse mutants of schizophrenia. Finally, we will determine whether the dendritic dysplasia of the SR mutant mice is reversible by treatments that enhance NMDA receptor function. It is our hope that by further characterizing the consequences of impaired NMDA receptor function in schizophrenia new targets for pharmacotherapeutic intervention will be identified that will address the recalcitrant negative symptoms and cognitive impairments.

Public Health Relevance

This project has developed evidence that a core abnormality in schizophrenia is reduced cortical neurotransmission via the NMDA subtype of glutamate receptor. The investigator has inactivated in mice in a cell specific manner a gene regulating the NMDA receptor and has shown that this results in abnormal cortical neurons similar to those found in schizophrenia. He will use the model to clarify the underlying mechanisms, to determine how these mechanisms relate to other schizophrenic risk genes and to test potential treatments to correct these neuronal defects characteristic of schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH051290-15
Application #
8196930
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
1994-08-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
15
Fiscal Year
2012
Total Cost
$395,000
Indirect Cost
$145,000
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Wolosker, Herman; Balu, Darrick T; Coyle, Joseph T (2016) The Rise and Fall of the d-Serine-Mediated Gliotransmission Hypothesis. Trends Neurosci 39:712-721
Kangas, Brian D; Bergman, Jack; Coyle, Joseph T (2016) Touchscreen assays of learning, response inhibition, and motivation in the marmoset (Callithrix jacchus). Anim Cogn 19:673-7
Coyle, Joseph T; Balu, Darrick T; Puhl, Matthew D et al. (2016) History of the Concept of Disconnectivity in Schizophrenia. Harv Rev Psychiatry 24:80-6
Balu, Darrick T; Li, Yan; Takagi, Shunsuke et al. (2016) An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia. Neuropsychopharmacology 41:2052-61
Takagi, Shunsuke; Balu, Darrick T; Coyle, Joseph T (2015) Subchronic pharmacological and chronic genetic NMDA receptor hypofunction differentially regulate the Akt signaling pathway and Arc expression in juvenile and adult mice. Schizophr Res 162:216-21
Puhl, Matthew D; Mintzopoulos, Dionyssios; Jensen, J Eric et al. (2015) In vivo magnetic resonance studies reveal neuroanatomical and neurochemical abnormalities in the serine racemase knockout mouse model of schizophrenia. Neurobiol Dis 73:269-74
Konopaske, Glenn T; Coyle, Joseph T (2015) Possible compensatory mechanisms for glutamatergic disconnection found in the auditory cortex in schizophrenia. Biol Psychiatry 77:923-4
Balu, Darrick T; Coyle, Joseph T (2015) The NMDA receptor 'glycine modulatory site' in schizophrenia: D-serine, glycine, and beyond. Curr Opin Pharmacol 20:109-15
Puhl, Matthew D; Berg, Alexandra R; Bechtholt, Anita J et al. (2015) Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse. J Pharmacol Exp Ther 353:465-70
Konopaske, Glenn T; Subburaju, Sivan; Coyle, Joseph T et al. (2015) Altered prefrontal cortical MARCKS and PPP1R9A mRNA expression in schizophrenia and bipolar disorder. Schizophr Res 164:100-8

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