SU98. Glutamate and GABA in the Substantia Nigra in Postmortem Brain

Abstract Background: Schizophrenia (SZ) is a mental illness that has positive, negative, and cognitive symptoms. The substantia nigra (SN) is one of the largest dopaminergic nuclei in the brain and projects to the striatum which is the primary locus for action of antipsychotic drugs. The SN receives both glutamatergic and GABAergic inputs that regulate the dopaminergic neuronal activity. In recent years, imaging studies that have shown hyperactivity of the SN in patients with SZ, suggesting that dysregulation of the SN may play of role in the increased amount of dopamine in the striatum in these patients. Methods: Our study examined neurochemically defined inputs to the SN. The postmortem SN that was used was collected from the Maryland Brain Collection. There were 11 cases total that were examined in this study with schizophrenia cases (n = 6) being compared to matched normal control cases (SZ) (n = 5). In this study, immunohistochemistry was performed with 3 different antibodies: vGLUT1, vGLUT2, and GAD67, which labels glutamatergic (vGLUT1 and vGLUT2) and GABAergic (GAD67) projections to the SN. VGLUT1 labels projections coming from cortical and hippocampal regions while vGLUT2 labels projections coming from subcortical regions such as the subthalamic nucleus and the pedunculopontine nucleus. The stained tissues were mounted, cover slipped, and the entirety of the SN was imaged using a light box. Three to 4 sections were analyzed per case. Using a random coordinate generator, 20 areas were selected from each section from which 25 photos were taken for each; optical densitometry (OD) analysis was performed using ImageJ. Results: The mean OD values for vGLUT1 were 16.1 ± 5.6 (NC) and 11.6 ± 6.6 (SZ); a 28% decrease for SZ. The mean OD values for vGLUT2 were 35.8 ± 3.9 (NC) and 41.1 ± 6.7 (SZ), a 15% increase for SZ. The mean OD values for GAD67 were 26.5 ± 13.4 (NC) and 32.2 ± 20.0 (SZ), a 21% increase for SZ. Conclusion: None of these changes reached statistical significance, due in part to the small sample size and great variation in results in the SZ group. A previous study from our lab showed changes in protein levels in the SN that were dependent on medication status. Ongoing studies include an electron microscopic analysis of mitochondria per terminal in the SZ, to determine if there are compromised energy demands in specific subsets of terminals.