Accumulating evidence suggests that negative symptoms of schizophrenia may be mediated by altered circuit activity in the amygdala;specifically the basolateral amygdala (BLA) -nucleus accumbens (NA) and BLA- central nucleus (CeA) connections. 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 function is linked to an array of neurocognitive 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 synaptic 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 dendritic 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 patients. In this project we will examine the NMDA receptor function using immunoprecipitation -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 a sociality, lead to poor outcome and we have little 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 underlying 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 #
5P50MH096891-02
Application #
8536951
Study Section
Special Emphasis Panel (ZMH1-ERB-S)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$304,921
Indirect Cost
$116,698
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Forrest, Alexandra D; Bang, Jakyung; Featherstone, Robert E et al. (2018) Pyramidal cell-selective GluN1 knockout causes impairments in salience attribution and related EEG activity. Exp Brain Res 236:837-846
Grunfeld, Itamar S; Likhtik, Ekaterina (2018) Mixed selectivity encoding and action selection in the prefrontal cortex during threat assessment. Curr Opin Neurobiol 49:108-115
Wang, Daifeng; Liu, Shuang; Warrell, Jonathan et al. (2018) Comprehensive functional genomic resource and integrative model for the human brain. Science 362:
Thomas, Michael L; Brown, Gregory G; Gur, Ruben C et al. (2018) A signal detection-item response theory model for evaluating neuropsychological measures. J Clin Exp Neuropsychol 40:745-760
Pehlivanova, Marieta; Wolf, Daniel H; Sotiras, Aristeidis et al. (2018) Diminished Cortical Thickness is Associated with Impulsive Choice in Adolescence. J Neurosci :
Gandal, Michael J; Zhang, Pan; Hadjimichael, Evi et al. (2018) Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science 362:
Agrawal, A; Chou, Y-L; Carey, C E et al. (2018) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry 23:1293-1302
Kaczkurkin, A N; Moore, T M; Calkins, M E et al. (2018) Common and dissociable regional cerebral blood flow differences associate with dimensions of psychopathology across categorical diagnoses. Mol Psychiatry 23:1981-1989
Baum, Graham L; Roalf, David R; Cook, Philip A et al. (2018) The impact of in-scanner head motion on structural connectivity derived from diffusion MRI. Neuroimage 173:275-286
Xia, Cedric Huchuan; Ma, Zongming; Ciric, Rastko et al. (2018) Linked dimensions of psychopathology and connectivity in functional brain networks. Nat Commun 9:3003

Showing the most recent 10 out of 87 publications