Project 2-Ermentrout investigates the functional properties and receptor subtypes mediating transmission at the inhibitory synaptic connections made by specific classes of GABA neurons in local circuits of the primate neocortex. The studies are motivated by the hypothesis that the presence of short- versus long-lasting inhibitory postsynaptic currents (IPSCs) at specific connections in the cortical network may associate the activity of certain interneuron subclasses with high (gamma, 30-80Hz) and low (theta, 4-8 Hz) frequency oscillations, respectively. Specifically, we suggest that fast spiking (FS) and non-fast-spiking (nFS) neurons signal via fast and slow IPSCs, respectively. In addition, we hypothesize that different subtypes of ionotropic GABA-A receptors underlie the fast and slow IPSCs in connections from FS and nFS neurons. In computational modeling studies, we will test the validity of the idea that fast and slow IPSCs may associate FS and nFS neurons with gamma and theta network oscillations. Electrophysiological studies in vitro will determine whether indeed FS and nFS neurons signal via fast and slow IPSCs. In addition, the subtypes of GABA-A receptors mediating the IPSCs at connections made by FS and nFS onto other cells of the neocortical network will be assessed using novel benzodiazepine-like compounds that act in a receptor subtype-selective manner. These investigations will be supported by quantitative anatomical studies of the subtype of GABA-A receptor at the different types of synaptic connections using immunocytochemical labeling and fluorescence microscopy techniques. The data obtained in the computer simulations and electrophysiological studies will be integrated in order to build a biophysically-based model of the neocortical network in which the effects of manipulating receptor subtypes is simulated. In light of the previously described alterations in GABA neurons and GABA-A receptor subtypes in schizophrenia, the studies in Project 2 will not only increase our understanding of interneuron function and dysfunction in the illness, but may also have predictive value in terms of future pharmacological interventions based on GABA-A receptor subtypes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
3P50MH084053-05S1
Application #
8500448
Study Section
Special Emphasis Panel (ZMH1-ERB-S)
Project Start
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$51,864
Indirect Cost
$7,919
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lizano, Paulo L; Yao, Jeffrey K; Tandon, Neeraj et al. (2017) Association of sFlt-1 and worsening psychopathology in relatives at high risk for psychosis: A longitudinal study. Schizophr Res 183:75-81
Agrawal, A; Chou, Y-L; Carey, C E et al. (2017) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry :
Mancuso, Nicholas; Shi, Huwenbo; Goddard, Pagé et al. (2017) Integrating Gene Expression with Summary Association Statistics to Identify Genes Associated with 30 Complex Traits. Am J Hum Genet 100:473-487
Jasinska, Anna J; Zelaya, Ivette; Service, Susan K et al. (2017) Genetic variation and gene expression across multiple tissues and developmental stages in a nonhuman primate. Nat Genet 49:1714-1721
Lewis, David A; Glausier, Jill R (2016) Alterations in Prefrontal Cortical Circuitry and Cognitive Dysfunction in Schizophrenia. Nebr Symp Motiv 63:31-75
Georgiev, Danko; Yoshihara, Toru; Kawabata, Rika et al. (2016) Cortical Gene Expression After a Conditional Knockout of 67 kDa Glutamic Acid Decarboxylase in Parvalbumin Neurons. Schizophr Bull 42:992-1002
Lizano, Paulo L; Keshavan, Matcheri S; Tandon, Neeraj et al. (2016) Angiogenic and immune signatures in plasma of young relatives at familial high-risk for psychosis and first-episode patients: A preliminary study. Schizophr Res 170:115-22
Li, Ming; Jaffe, Andrew E; Straub, Richard E et al. (2016) A human-specific AS3MT isoform and BORCS7 are molecular risk factors in the 10q24.32 schizophrenia-associated locus. Nat Med 22:649-56
Kimoto, Sohei; Glausier, Jill R; Fish, Kenneth N et al. (2016) Reciprocal Alterations in Regulator of G Protein Signaling 4 and microRNA16 in Schizophrenia. Schizophr Bull 42:396-405
Fromer, Menachem; Roussos, Panos; Sieberts, Solveig K et al. (2016) Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci 19:1442-1453

Showing the most recent 10 out of 98 publications