This is a revised competing renewal of a project studying the synaptic organization of postmortem striatum in schizophrenic subjects (SZ) at the ultrastructural level. The striatum, which interacts with other brain areas to affect motor, cognitive and limbic behavior, is one of the regions affected in schizophrenia. The results of the studies in the last grant cycle indicated an increase in cortico-striatal type synapses in the caudate matrix and putamen patches, that was not caused by antipsychotic medication. The higher density of cortical-type synapses in the SZ cases than in controls suggests hyper-stimulation of striatal projection neurons. This could have several important and different downstream effects depending on the precise circuitry involved. The present application seeks to identify the specific striatal circuitry affected in SZ. SA#1) To test the hypothesis that limbic and prefrontal circuitry are perturbed at the level of the striatum, we will examine synaptic density in the subregions of the striatum that process these circuits. SA2 will examine synaptic density of striatonigral and striatopallidal neurons in the patch and matrix in select striatal territories determined in SA1. SA#2A) To test the hypothesis that striatopallidal matrix neurons in the caudate receive more excitatory inputs, the immunocytochemical localization of enkephalin, a marker of these neurons, will be performed;the number of synapses formed onto labeled spines will be compared between groups. SA#2B) Tests the hypotheses that striatonigral matrix neurons in the caudate receive more excitatory inputs, but that striatonigral neurons in the putamen patch receive normal or fewer numbers of synapses. The immunocytochemical localization of substance P, a marker of striatonigral neurons, will be performed;the number of synapses formed onto labeled spines will be compared between groups. SA#3) To test the hypothesis that typical vs atypical APDs have different effects on the patch and matrix compartment, we will treat rats chronically with APDs, process the tissue for calbindin immunocytochemistry to identify the patch and matrix and analyze EM samples obtained from each. In monkey tissue obtained from Dr. Lewis, we will examine the synaptic density (labeled with synaptophysin) within the patch and matrix compartments in chronic haldol treated animals and controls using light microscopy. The proposed experiments will: 1) distinguish between drug effects and disease related alterations in synaptic pathology;2) will provide insight into the mechanisms of action of antipsychotic drugs;and 3) are an important initial step in identifying putative abnormal striatal circuitry that may underlie some of the psychopathology of schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH060744-11
Application #
7809463
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
1999-12-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
11
Fiscal Year
2010
Total Cost
$316,789
Indirect Cost
Name
University of Alabama Birmingham
Department
Psychiatry
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
McCollum, Lesley A; Roche, Joy K; Roberts, Rosalinda C (2012) Immunohistochemical localization of enkephalin in the human striatum: a postmortem ultrastructural study. Synapse 66:204-19
Somerville, Shahza M; Conley, Robert R; Roberts, Rosalinda C (2012) Striatal mitochondria in subjects with chronic undifferentiated vs. chronic paranoid schizophrenia. Synapse 66:29-41
Somerville, Shahza M; Conley, Robert R; Roberts, Rosalinda C (2011) Mitochondria in the striatum of subjects with schizophrenia. World J Biol Psychiatry 12:48-56
Somerville, Shahza M; Lahti, Adrienne C; Conley, Robert R et al. (2011) Mitochondria in the striatum of subjects with schizophrenia: relationship to treatment response. Synapse 65:215-24
Barksdale, Keri A; Perez-Costas, Emma; Gandy, Johanna C et al. (2010) Mitochondrial viability in mouse and human postmortem brain. FASEB J 24:3590-9
Perez-Costas, Emma; Gandy, Johanna C; Melendez-Ferro, Miguel et al. (2010) Light and electron microscopy study of glycogen synthase kinase-3beta in the mouse brain. PLoS One 5:e8911
Dwivedi, Yogesh; Rizavi, Hooriyah S; Zhang, Hui et al. (2010) Modulation in activation and expression of phosphatase and tensin homolog on chromosome ten, Akt1, and 3-phosphoinositide-dependent kinase 1: further evidence demonstrating altered phosphoinositide 3-kinase signaling in postmortem brain of suicide subject Biol Psychiatry 67:1017-25
Perez-Costas, Emma; Melendez-Ferro, Miguel; Roberts, Rosalinda C (2010) Basal ganglia pathology in schizophrenia: dopamine connections and anomalies. J Neurochem 113:287-302
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
Melendez-Ferro, Miguel; Perez-Costas, Emma; Roberts, Rosalinda C (2009) A new use for long-term frozen brain tissue: golgi impregnation. J Neurosci Methods 176:72-7

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