Reduction of the synaptic protein rab3a in the thalamus and connecting brain regions in post-mortem schizophrenic brains

Although the psychotic symptoms in schizophrenia can be alleviated by treat ment with dopaminergic receptor antagonists, the etiology and underlying ne urochemical pathology remains obscure. Both neuropathological and magnetic resonance imaging studies have found evidence for neuronal loss and atrophy in the thalamus in schizophrenia, implicating this key structure for gatin g information to cortical areas in the pathophysiology. Recent studies have also found evidence of synaptic loss in the thalamus in schizophrenia. To further examine possible synaptic disturbances, we studied the synaptic rel ated protein rab3a as a marker for synaptic density, using both quantitativ e Western blotting and immunohistochemistry. The material consisted of brai ns from 22 schizophrenic patients (mean age 79.3 years), and 24 control sub jects (74.8 years). Reduced rab3a protein levels were found in the left tha lamus in schizophrenia (0.47 +/- 0.17 vs. 1.00 +/- 0.18; p < 0.0001), while a less marked decrease was found also in the right thalamus (0.75 +/- 0.13 vs. 1.00 +/- 0.09; p < 0.0001). Immunohistochemistry, performed on two sch izophrenic and two control brains, revealed that rab3a immunoreactivity was most reduced in the left anterior and mediodorsal thalamic nuclei. Therefo re, we extended the study to brain regions connected these thalamic nuclei. Reduced rab3a protein levels were found schizophrenia also in the frontal cortex, hippocampus, gyrus cinguli, and parietal cortex, while no significa nt differences were found in the temporal cortex, or in cerebellum. The red uction in rab3a was not found to be secondary to confounding factors such a s age-differences, post-mortem delay time, generalized brain atrophy, or an tipsychotic medication. Therefore, the reduction of rab3a probably reflects synaptic disturbances, possibly synaptic loss, in the limbic system and ne ocortical areas, in schizophrenia. This part of the brain is known to be in volved in behavioral and emotional control, and thus to be crucial for high er mental functions, suggesting that synaptic disturbances in the limbic ma y be of importance in the development of psychotic symptoms in schizophreni a.