Re-arrangements of gene transcripts at glutamatergic synapses after prolonged treatments with antipsychotics: A putative link with synaptic remodeling

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Objectives:The postsynaptic density (PSD) represents a site of dopamine-glutamate integration. Despite multiple evidence of PSD involvement in antipsychotic-induced synaptic changes, there are no direct head-to-head comparisons of the effects at the PSD of antipsychotics with different receptor profile and at different doses after chronic administration.Methods:Molecular imaging of gene expression was used to investigate whether chronic treatment with first and second generation antipsychotics (haloperidol, asenapine and olanzapine) may induce changes in the expression levels of PSD transcripts involved in schizophrenia pathophysiology, i.e. Homers, Shank1, PSD-95 and Arc.Results:Genes' expression patterns were differentially modulated after chronic administration of typical and atypical antipsychotics as well as by the same compound administered at different doses. Antipsychotic treatment reduced gene expression in cortical regions, while Homer1a was still induced in striatum by haloperidol even after prolonged treatment. Moreover, chronic treatments appeared to cause a “de-recruitment” of brain regions demonstrated to be activated in acute treatments, with a prominent effect in the cortex rather than in striatum.Conclusions:These results let hypothesize that prolonged antipsychotic treatment may trigger a set of plastic changes involving scaffolding and effector molecules causing a possible re-arrangement of PSD transcripts in brain regions relevant to schizophrenia pathophysiology.HighlightsChronic antipsychotics at different doses may impact synaptic plasticity genes.Molecular imaging is used to test haloperidol, asenapine and olanzapine effects.Homers, Shank1, PSD-95 and Arc expression levels are differentially modulated.Antipsychotics trigger molecular changes in brain regions linked to schizophrenia.

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