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

被引:108
作者
de Bartolomeis, Andrea [1 ]
Latte, Gianmarco [1 ]
Tomasetti, Carmine [1 ]
Iasevoli, Felice [1 ]
机构
[1] Univ Naples Federico II, Sch Med, Dept Neurosci Reprod & Odontostomatol Sci,Sect Ps, Lab Mol & Translat Psychiat,Unit Treatment Resist, I-80131 Naples, Italy
关键词
Psychosis; Antipsychotics; Synapse; PSD-95; Homer; Shank; LONG-TERM DEPRESSION; INTERACTING PSD PROTEINS; DISC1 TRANSGENIC MICE; NMDA RECEPTOR SUBUNIT; GENETIC MOUSE MODELS; PREFRONTAL CORTEX; MESSENGER-RNA; ANTIPSYCHOTIC-DRUGS; DIFFERENTIAL EXPRESSION; EXCITATORY SYNAPSE;
D O I
10.1007/s12035-013-8534-3
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:484 / 511
页数:28
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