This application seeks to identify and characterize the nature and localization of anatomic and chemical abnormalities in the limbic cortex of schizophrenic (hippocampus, entorhinal cortex, and anterior cingulate) contributing to the pathophysiology of the disease. Several laboratories have generated data suggesting limbic pathology in schizophrenia; our own in vivo imaging and postmortem studies (see Prelim Data) suggest a limbic focus as well. Recently, data from Csernansky et al, have suggested that pathology in the hippocampus is not homogeneous, but is localized within that structure to the lateral head of the hippocampus and the medial aspect of the body (subiculum); this might explain the variability of outcomes reported across studies in postmortem analyses, because few studies control for hippocampal axis. To answer this question, we have paired anatomic and neurochemical measures within the hippocampus, entorhinal cortex, and anterior cingulate from anterior to posterior extent, quantifying markers of neuronal structure and transmission, which may be abnormal in schizophrenic limbic cortex. The hypothesis driving this work is based on our in vivo imaging data from patient studies and our animal model work, which are extensively in agreement with the published literature. We have raised the speculative hypothesis that positive symptoms in schizophrenia are associated with reduced glutamatergic activity at the NMDA receptor in the hippocampus. The resulting reduction in the activity of the glutamatergic hippocampal efferent signal to its projection fields, including entorhinal cortex, anterior thalamus, and anterior cingulate may underlie the generation of psychotic symptoms in schizophrenia. 24 postmortem schizophrenia brains with paired EC, hippocampi and cingulates will be compared to the same structures in 24 matched healthy and 12 matched psychotic control brains. We will study neuronal number, synaptic and dendritic density, along with neurochemical measures of the glutamate, and GABA, systems along the A-P- extent of these structures. We postulate that only certain regions of hippocampus will be affected (lateral head and medial body), and that the neurochemical abnormalities in these regions will colocalize with neuronal number and/or synaptic and dendritic changes, and that related regions of hippo, EC, and ACC will be affected. These data will have implications for understanding the mechanisms of the illness and for directing future new drug discovery for schizophrenia therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH062236-05
Application #
7017089
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Meinecke, Douglas L
Project Start
2002-02-01
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2008-01-31
Support Year
5
Fiscal Year
2006
Total Cost
$282,795
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Psychiatry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Segev, Amir; Yanagi, Masaya; Scott, Daniel et al. (2018) Reduced GluN1 in mouse dentate gyrus is associated with CA3 hyperactivity and psychosis-like behaviors. Mol Psychiatry :
Li, Wei; Ghose, Subroto; Gleason, Kelly et al. (2015) Synaptic proteins in the hippocampus indicative of increased neuronal activity in CA3 in schizophrenia. Am J Psychiatry 172:373-82
Yanagi, M; Joho, R H; Southcott, S A et al. (2014) Kv3.1-containing K(+) channels are reduced in untreated schizophrenia and normalized with antipsychotic drugs. Mol Psychiatry 19:573-9
Tamminga, Carol A; Southcott, Sarah; Sacco, Carolyn et al. (2012) Glutamate dysfunction in hippocampus: relevance of dentate gyrus and CA3 signaling. Schizophr Bull 38:927-35
Tamminga, Carol A; Thomas, Binu P; Chin, Ronald et al. (2012) Hippocampal novelty activations in schizophrenia: disease and medication effects. Schizophr Res 138:157-63
Alexander, Brian; Warner-Schmidt, Jennifer; Eriksson, Therese et al. (2010) Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens. Sci Transl Med 2:54ra76
Tamminga, Carol A; Stan, Ana D; Wagner, Anthony D (2010) The hippocampal formation in schizophrenia. Am J Psychiatry 167:1178-93
Gao, Xue-Min; Elmer, Gregory I; Adams-Huet, Beverley et al. (2009) Social memory in mice: disruption with an NMDA antagonist and attenuation with antipsychotic drugs. Pharmacol Biochem Behav 92:236-42
Ghose, Subroto; Gleason, Kelly A; Potts, Bryan W et al. (2009) Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia: a mechanism for antipsychotic drug action? Am J Psychiatry 166:812-20
Ghose, Subroto; Chin, Ronald; Gallegos, Analysa et al. (2009) Localization of NAAG-related gene expression deficits to the anterior hippocampus in schizophrenia. Schizophr Res 111:131-7

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