Emerging researches point to a relevant role of postsynaptic density (PSD)
proteins, such as PSD-95, Homer, Shank, and DISC-1, in the pathophysiology of
schizophrenia and
autism spectrum disorders. The PSD is a thickness, detectable at electronic microscopy, localized at the postsynaptic membrane of glutamatergic synapses, and made by scaffolding
proteins, receptors, and effector
proteins; it is considered a structural and functional crossroad where multiple
neurotransmitter systems converge, including the dopaminergic, serotonergic, and glutamatergic ones, which are all implicated in the pathophysiology of
psychosis. Decreased
PSD-95 protein levels have been reported in postmortem brains of
schizophrenia patients. Variants of Homer1, a key PSD
protein for
glutamate signaling, have been associated with
schizophrenia symptoms severity and therapeutic response. Mutations in Shank gene have been recognized in
autism spectrum disorder patients, as well as reported to be associated to behaviors reminiscent of
schizophrenia symptoms when expressed in genetically engineered mice. Here, we provide a critical appraisal of PSD
proteins role in the pathophysiology of
schizophrenia and
autism spectrum disorders. Then, we discuss how
antipsychotics may affect PSD
proteins in brain regions relevant to
psychosis pathophysiology, possibly by controlling synaptic plasticity and dendritic spine rearrangements through the modulation of
glutamate-related targets. We finally provide a framework that may explain how PSD
proteins might be useful candidates to develop new therapeutic approaches for
schizophrenia and related disorders in which there is a need for new
biological treatments, especially against some symptom domains, such as negative symptoms, that are poorly affected by current
antipsychotics.