Accumulating evidence suggests that negative symptoms of schizophrenia may be mediated by altered circuit acfivity in the amygdala;specifically the basolateral amygdala (BLA) -nucleus accumbens (NA) and BLA- central nucleus (CeA) connecfions. Given that circuit activity is governed by synaptic strength/plasticity, NMDA receptor function, a key modulator of synaptic plasticity, may play a pivotal role in the BLA-NA and BLA-CeA circuitry. NMDA receptor funcfion is linked to an array of neurocognifive functions and can induce endophenotypic behaviors of schizophrenia when perturbed in specific brain regions. We postulate that altered synaptic connectivity associated with dysregulated NMDA receptor function in the BLA-NA and BLA- CeA circuitry may lead to negative symptoms of schizophrenia. The BLA circuitry receives robust Dl and D2R mediated input from the prefrontal cortex and striatum and its overall activity is regulated by feedfoward and feedback inhibition via GABAergic neurons in intercalated islands. Cell type specific assessment of dopaminergic and NMDA receptor signaling therefore can reveal the intercellular dynamics leading to faulty circuitry of the amygdala in schizophrenia. To address this, we propose a postmortem study in which we conduct histologic and biochemical assessment of the synapfic strength and signaling activity of NMDA and dopaminergic receptors in a cell type specific manner. In the postmortem amygdala of 30 schizophrenia subjects and their matched controls, we will examine dendrific spine density and the integrity of synapses in principal and interneurons separately. Evaluation of receptor signaling in postmortem brains has been a challenging task. We have recently developed a number of paradigms that permit us to do so and found attenuation in tyrosine phosphorylation of NMDAR2A/2B reduced Src activity and altered protein interactions of NMDA receptor complexes in the PFC of SCZ pafients. In this project we will examine the NMDA receptor function using immunoprecipitafion -SRM-Mass spec analysis. Dopaminergic signaling can impact on NMDA receptor signaling in principal and interneurons modulating the overall circuit activity. We will examine presynaptic and postsynaptic segments of dopaminergic input using histologic and biochemical assessment.

Public Health Relevance

Negative symptoms of schizophrenia, including lack of motivation and asociality, lead to poor outcome and we have littie insight into their biology and treatment. We postulate that negative symptoms are caused by altered circuit activity in the amygdala via dysregulated synaptic connectivity and NMDA receptor signaling. Postmortem studies will elucidate molecular mechanisms undertying faulty circuit activity of the amygdala in schizophrenia

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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University of Pennsylvania
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