Glutamatergic Postsynaptic Density Protein Dysfunctions in Synaptic Plasticity and Dendritic Spines Morphology: Relevance to Schizophrenia and Other Behavioral Disorders Pathophysiology, and Implications for Novel Therapeutic Approaches

Mol Neurobiol. 2014 Feb;49(1):484-511. doi: 10.1007/s12035-013-8534-3. Epub 2013 Sep 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antipsychotic Agents / administration & dosage
  • Child Development Disorders, Pervasive / drug therapy
  • Child Development Disorders, Pervasive / metabolism
  • Child Development Disorders, Pervasive / physiopathology
  • Dendritic Spines / metabolism*
  • Dendritic Spines / pathology
  • Disks Large Homolog 4 Protein
  • Drug Delivery Systems / trends
  • Glutamic Acid / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / metabolism
  • Mental Disorders / drug therapy
  • Mental Disorders / metabolism
  • Mental Disorders / physiopathology
  • Nerve Tissue Proteins / metabolism*
  • Neuronal Plasticity / physiology*
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism*
  • Schizophrenia / physiopathology
  • Synapses / metabolism*
  • Synapses / pathology

Substances

  • Antipsychotic Agents
  • DLG4 protein, human
  • Disks Large Homolog 4 Protein
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • postsynaptic density proteins
  • Glutamic Acid