The Glutamatergic Aspects of Schizophrenia Molecular Pathophysiology: Role of the Postsynaptic Density, and Implications for Treatment
Felice Iasevoli, Carmine Tomasetti, Elisabetta F. Buonaguro and Andrea de Bartolomeis
Affiliation: Department of Neuroscience, Reproductive and Odontostomatological Sciences, University “Federico II” of Naples, Via Pansini 5, 80131 Napoli, Italy.
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
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
Keywords: Dopamine, homer, kalirin, NMDA, PSD-95, psychosis, shank, synaptic plasticity.
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