The glutamatergic aspects of schizophrenia molecular pathophysiology: role of the postsynaptic density, and implications for treatment

Abstract

Schizophrenia is one of the most debilitating psychiatric diseases with a lifetime prevalence of approximately 1%. Although the specific molecular underpinnings of schizophrenia are still unknown, evidence has long linked its pathophysiology to postsynaptic abnormalities. The postsynaptic density (PSD) is among the molecular structures suggested to be potentially involved in schizophrenia. More specifically, the PSD is an electron-dense thickening of glutamatergic synapses, including ionotropic and metabotropic glutamate receptors, cytoskeletal and scaffolding proteins, and adhesion and signaling molecules. Being implicated in the postsynaptic signaling of multiple neurotransmitter systems, mostly dopamine and glutamate, the PSD constitutes an ideal candidate for studying dopamine-glutamate disturbances in schizophrenia. Recent evidence suggests that some PSD proteins, such as PSD-95, Shank, and Homer are implicated in severe behavioral disorders, including schizophrenia. These findings, further corroborated by genetic and animal studies of schizophrenia, offer new insights for the development of pharmacological strategies able to overcome the limitations in terms of efficacy and side effects of current schizophrenia treatment. Indeed, PSD proteins are now being considered as potential molecular targets against this devastating illness. The current paper reviews the most recent hypotheses on the molecular mechanisms underlying schizophrenia pathophysiology. First, we review glutamatergic dysfunctions in schizophrenia and we provide an update on postsynaptic molecules involvement in schizophrenia pathophysiology by addressing both human and animal studies. Finally, the possibility that PSD proteins may represent potential targets for new molecular interventions in psychosis will be discussed.

Keywords: Dopamine; NMDA; PSD-95; homer; kalirin; psychosis; shank; synaptic plasticity..

Fig. (1)

Schematic Representation of the Postsynaptic Density. In this picture, we provide a simplified representation of a postsynaptic density (PSD) ultrastructure. For the sake of clarity, ultracellular organelles as well as less relevant proteins are not depicted. The call-outs describe the pathophysiological role of the proteins discussed in the text. NMDAR: N-methyl-D-Aspartate Receptor. EphR: Ephrin Receptor. AMPAR: Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Receptor. VGCC: Voltage-Gated Calcium Channel. mGluR1a/5: type 1a/5 metabotropic glutamate receptor. TRPC: Transient Receptor Potential Cation channels. GRIP: Glutamate Receptor Interacting Protein. CaMKII: Calcium/Calmodulin-Dependent Kinase II. Rac: Ras-related C3 botulinum toxin substrate. GKAP: Guanylate Kinase-Associated Protein. EVH1: Ena/VASP Homology 1 domain. TANC: TRP- ankyrin repeat- and coiled-coil region containing protein. AKAP: A-Kinase Anchor Protein. PIP2: phosphatidylinositol biphosphate. IP3: inositol triphosphate. IP3R: IP3 Receptor. DAG: Diacylglycerol.