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
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
Santini, Martin A; Balu, Darrick T; Puhl, Matthew D et al. (2014) D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI. Behav Brain Res 259:242-6
Balu, Darrick T; Coyle, Joseph T (2014) Chronic D-serine reverses arc expression and partially rescues dendritic abnormalities in a mouse model of NMDA receptor hypofunction. Neurochem Int 75:76-8
Balu, Darrick T; Li, Yan; Puhl, Matthew D et al. (2013) Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc Natl Acad Sci U S A 110:E2400-9
Li, Yan; Sacchi, Silvia; Pollegioni, Loredano et al. (2013) Identity of endogenous NMDAR glycine site agonist in amygdala is determined by synaptic activity level. Nat Commun 4:1760
Benneyworth, Michael A; Li, Yan; Basu, Alo C et al. (2012) Cell selective conditional null mutations of serine racemase demonstrate a predominate localization in cortical glutamatergic neurons. Cell Mol Neurobiol 32:613-24
Balu, Darrick T; Coyle, Joseph T (2012) Neuronal D-serine regulates dendritic architecture in the somatosensory cortex. Neurosci Lett 517:77-81
Benneyworth, Michael A; Roseman, Alexander S; Basu, Alo C et al. (2011) Failure of NMDA receptor hypofunction to induce a pathological reduction in PV-positive GABAergic cell markers. Neurosci Lett 488:267-71
Balu, Darrick T; Coyle, Joseph T (2011) Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci Biobehav Rev 35:848-70
Coyle, Joseph T; Balu, Darrick; Benneyworth, Michael et al. (2010) Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia. Dialogues Clin Neurosci 12:359-82

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