Immediate-Early Genes Modulation by Antipsychotics: Translational Implications for a Putative Gateway to Drug-Induced Long-Term Brain Changes

Abstract

An increasing amount of research aims at recognizing the molecular mechanisms involved in long-lasting brain architectural changes induced by antipsychotic treatments. Although both structural and functional modifications have been identified following acute antipsychotic administration in humans, currently there is scarce knowledge on the enduring consequences of these acute changes. New insights in immediate-early genes (IEGs) modulation following acute or chronic antipsychotic administration may help to fill the gap between primary molecular response and putative long-term changes. Moreover, a critical appraisal of the spatial and temporal patterns of IEGs expression may shed light on the functional “signature” of antipsychotics, such as the propensity to induce motor side effects, the potential neurobiological mechanisms underlying the differences between antipsychotics beyond D2 dopamine receptor affinity, as well as the relevant effects of brain region-specificity in their mechanisms of action. The interest for brain IEGs modulation after antipsychotic treatments has been revitalized by breakthrough findings such as the role of early genes in schizophrenia pathophysiology, the involvement of IEGs in epigenetic mechanisms relevant for cognition, and in neuronal mapping by means of IEGs expression profiling. Here we critically review the evidence on the differential modulation of IEGs by antipsychotics, highlighting the association between IEGs expression and neuroplasticity changes in brain regions impacted by antipsychotics, trying to elucidate the molecular mechanisms underpinning the effects of this class of drugs on psychotic, cognitive and behavioral symptoms.

Towards Novel Treatments for Schizophrenia: Molecular and Behavioural Signatures of the Psychotropic Agent SEP-363856

“…We found that an acute treatment with SEP-856 produced a marked elevation of a number of activity dependent genes (IEGs), such as Arc , c-Fos , Zif268/Egr1 and Npas4 , under basal conditions in the prefrontal cortex, and much less in other structures. In line with our data, IEGs expression throughout the brain in response to antipsychotic challenge has been extensively investigated showing region-specific modulations of IEGs expression after antipsychotic treatments [ 26 ]. Specifically, atypical antipsychotics such as clozapine induced limbic and prefrontal cortical IEGs expression, whereas a substantial induction in the striatum was found following haloperidol administration [ 27 ].…”

Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

“…Furthermore, geneM21/isoM30 expression was negatively correlated with the degree of lifetime antipsychotic exposure in the subset of patients for whom these data were available (P=0.001, Pearson; Fig S11B). As such, it will be worthwhile to determine whether this module is a core driver of the therapeutic response, as has been suggested (65). Other neuronal modules distinguished SCZ and BD from ASD (Fig 5B), including geneM7, enriched for synaptic and metabolic processes with the splicing regulator NOVA2 (Fig 5C).…”

Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia

“…The role of glycine neurotransmission in the modulation of Homer gene expression has been explored in reference to the action of antipsychotics, alone or with the adjunction of glycine B-site agonists such as D-cycloserine (187). Multiple lines of evidence suggest an involvement of Homer (long and short forms, and their splicing variants) in antipsychotics action at level of PSD (188)(189)(190)(191). Polese et al have shown how add-on Dcycloserine to typical (haloperidol) and atypical (clozapine) antipsychotic treatment, modulate the expression of Homer 1a, in a negative trend in caudate-putamen (187).…”