The Effects of Antipsychotics on the Synaptic Plasticity Gene Homer1a Depend on a Combination of Their Receptor Profile, Dose, Duration of Treatment, and Brain Regions Targeted

Abstract

Background: Antipsychotic agents modulate key molecules of the postsynaptic density (PSD), including the Homer1a gene, implicated in dendritic spine architecture. How the antipsychotic receptor profile, dose, and duration of administration may influence synaptic plasticity and the Homer1a pattern of expression is yet to be determined. Methods: In situ hybridization for Homer1a was performed on rat tissue sections from cortical and striatal regions of interest (ROI) after acute or chronic administration of three antipsychotics with divergent receptor profile: Haloperidol, asenapine, and olanzapine. Univariate and multivariate analyses of the effects of topography, treatment, dose, and duration of antipsychotic administration were performed. Results: All acute treatment regimens were found to induce a consistently higher expression of Homer1a compared to chronic ones. Haloperidol increased Homer1a expression compared to olanzapine in striatum at the acute time-point. A dose effect was also observed for acute administration of haloperidol. Conclusions: Biological effects of antipsychotics on Homer1a varied strongly depending on the combination of their receptor profile, dose, duration of administration, and throughout the different brain regions. These molecular data may have translational valence and may reflect behavioral sensitization/tolerance phenomena observed with prolonged antipsychotics.

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

“…In this case, the high variability detected between studies could be mostly explained by the combination of multiple factors. Among others, different drug doses, acute or chronic administrations, and genes’ specificity were the main variables involved in determining heterogeneity [ 78 , 79 , 85 , 87 , 179 ].…”

Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal

“…Striatal expression of the Homer1a inducible transcript has been found selectively induced by D2R antagonism [ 233 ], and antipsychotic administration differentially regulated Homer1 gene expression according to the distinct gene isoform, brain region, antipsychotic type, and administration timing [ 234 , 235 , 236 , 237 ]. Notably, Homer1a has been used as a marker of glutamatergic activity to provide network maps of brain functions in relation to antipsychotic administration [ 238 ].…”

Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment

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