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

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
1P50MH096891-01
Application #
8443532
Study Section
Special Emphasis Panel (ZMH1-ERB-S (02))
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$292,838
Indirect Cost
$112,074
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gennatas, Efstathios D; Avants, Brian B; Wolf, Daniel H et al. (2017) Age-Related Effects and Sex Differences in Gray Matter Density, Volume, Mass, and Cortical Thickness from Childhood to Young Adulthood. J Neurosci 37:5065-5073
Schoch, Hannah; Kreibich, Arati S; Ferri, Sarah L et al. (2017) Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene. Biol Psychiatry 81:193-202
Chang, X; Liu, Y; Hahn, C-G et al. (2017) RNA-seq analysis of amygdala tissue reveals characteristic expression profiles in schizophrenia. Transl Psychiatry 7:e1203
Agrawal, A; Chou, Y-L; Carey, C E et al. (2017) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry :
White, Lauren K; Moore, Tyler M; Calkins, Monica E et al. (2017) An Evaluation of the Specificity of Executive Function Impairment in Developmental Psychopathology. J Am Acad Child Adolesc Psychiatry 56:975-982.e3
Mihara, Takuma; Mensah-Brown, Kobina; Sobota, Rosanna et al. (2017) Amygdala activity associated with social choice in mice. Behav Brain Res 332:84-89
Kaczkurkin, A N; Moore, T M; Calkins, M E et al. (2017) Common and dissociable regional cerebral blood flow differences associate with dimensions of psychopathology across categorical diagnoses. Mol Psychiatry :
Ciric, Rastko; Wolf, Daniel H; Power, Jonathan D et al. (2017) Benchmarking of participant-level confound regression strategies for the control of motion artifact in studies of functional connectivity. Neuroimage 154:174-187
Honnorat, N; Satterthwaite, T D; Gur, R E et al. (2017) sGraSP: A graph-based method for the derivation of subject-specific functional parcellations of the brain. J Neurosci Methods 277:1-20
Moore, Tyler M; Risbrough, Victoria B; Baker, Dewleen G et al. (2017) Effects of military service and deployment on clinical symptomatology: The role of trauma exposure and social support. J Psychiatr Res 95:121-128

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