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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

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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.

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Acknowledgments

All members of the Laboratory of Molecular and Translational Psychiatry contributed to ideas and comments on the present work.

Conflict of Interest

Andrea de Bartolomeis has received unrestricted research funding from Astra Zeneca, Janssen-Cilag, and Lundbeck. The funding was made available to the Department of Neuroscience, University of Naples Federico II. He has received honoraria as speaker at educational activity sponsored by Astra-Zeneca Italia, Janssen-Cilag Italy, Eli Lilly, and Bristol-Myers Squibb.

All other authors declare that, except for income received from our primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

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  1. Laboratory of Molecular and Translational Psychiatry, Unit of Treatment Resistant Psychosis, Department of Neuroscience, Reproductive and Odontostomatologic Sciences, Section of Psychiatry, University School of Medicine “Federico II”, Via Pansini 5, 80131, Naples, Italy

    Andrea de Bartolomeis, Andrea de Bartolomeis, Gianmarco Latte, Carmine Tomasetti & Felice Iasevoli

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de Bartolomeis, A., Latte, G., Tomasetti, C. et al. 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 49, 484–511 (2014). https://doi.org/10.1007/s12035-013-8534-3

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