A complex network of postsynaptic density (PSD) proteins mediate the targeting, anchoring, and spatial organization of synaptic proteins, including receptors, at the cell membrane of the glutamatergic synapse.  These proteins can also alter receptor sensitivity to glutamate, and modulate signaling cascades in glutamatergic synaptic transmission by linking the receptors to other critical intracellular effector molecules.  Pharmacological and anatomical evidence suggest that abnormal glutamate neurotransmission may be associated with the pathophysiology of schizophrenia and the mood disorders.  Changes in ionotropic receptor expression have occasionally been found in the prefrontal cortex in schizophrenia, but recently, we found that changes in the expression of PSD proteins are more robust.  We use in situ hybridization to determine NMDA (PSD95, NF-L, and SAP102) and AMPA (NSF, PICK-1, stargazin, and syntenin) associated PSD protein expression in the dorsolateral prefrontal cortex in subjects with schizophrenia, bipolar disorder, or major depression, using tissue from the Stanley Foundation Neuropathology Consortium.  To evaluate mRNA expression at the cellular level, we used high-resolution autoradiographic analysis by coating hybridized tissue sections with Kodak NTB-2 nuclear emulsion, and counting grains/cell using MCID Image system.   Also protein analysis by western blott and coimmunoprecipitation from postmortem tissue of the same cohorts are being conducted.  Our results suggest that there are disorder-specific abnormalities in the expression of some PSD proteins, including PICK1, stargazin and syntenin, in glutamatergic synapses in the prefrontal and/or cingulate cortex that are restricted to certain layers and cell types.  As a result of these alterations, glutamate receptor function may be altered and result in disturbances in signaling cascades associated with glutamate-mediated synaptic transmission in cortical circuits.

Monica Beneyto