The N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis is one of the leading postulates for the pathophysiology of schizophrenia (SCZ) and is supported by numerous pharmacologic, behavioral and genetic studies. Nevertheless, we have little insight into specific alterations in NMDAR signaling and its mechanistic basis in SCZ patients. This is a critical knowledge gap, which has impeded further development of this hypothesis and limited our efforts to identify specific therapeutic interventions. (Preliminary Data) As direct evidence for altered NMDA receptor (NMDAR) signaling, we found decreased NMDA/Glycine induced tyrosine phosphorylation of NMDAR subunit 2 (GluN2) and reduced downstream signaling in the postmortem dorsal lateral prefrontal cortex (DLPFC) of SCZ cases. These changes are not associated with decreased NMDARs but with reduced activity of a cascade of kinases- Src kinase, protein kinase C and Pyk2- which in concert decrease GluN2 tyrosine phosphorylation. We found multiple molecular alterations in the DLPFC of SCZ cases; increased PSD-95, increased erbB4 activity, decreased dysbindin -1 and RPTPa, each of which can induce Src hypoactivity. (Hypotheses) We hypothesize that hypoactivity of Src in the NMDAR complex (Src-NR) reduces GluN tyrosine phosphorylation and is caused by altered protein interactions in a network of Src-NR-associated proteins ( the Src-NR interactome), which can be leveraged to modify behavioral phenotypes of NMDAR hypoactivity. (Approach) We propose a human-rodent translation strategy, by which we analyze disease related alterations in postmortem brains and examine their underlying mechanisms in rodent studies.
Aim 1 will further examine postmortem brains of an elderly and mid-life SCZ cohorts to identify molecular alterations in the Src-NR interactome in SCZ, Aim 2 will determine the role of protein interactions in Src-NR hypoactivity and test rescue strategies in ex vivo preparations of rodent and human postmortem tissues and Aim 3 will determine SCZ related behavior and EEG phenotypes of Src-/- mice and test if Src enhancement can rescue such phenotypes in vivo.

Public Health Relevance

There are multiple lines of evidence that N-methyl-D-aspartate (NMDA) receptor function is decreased in brains of patients with schizophrenia causing various symptoms of the illness. Nevertheless, we have little insight into how exactly the NMDA receptor system is altered in schizophrenia and what are the causative mechanisms. We present the evidence that NMDA hypofunction in schizophrenia is due to decreased activity of Src kinase, which is caused by dysregulations of genes that have been implicated for schizophrenia. The goal of this project is to investigate underlying mechanisms for these findings, which could lead to a better understanding of the illness as well as to a possible therapeutic strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH075916-08
Application #
9420642
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2005-12-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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