Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects

Abstract

Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

“…These data suggest that antipsychotic medication usage did not drive [ 11 C]Martinostat uptake alterations in these regions. As antipsychotic drug exposure was shown to increase HDAC2 protein expression in the frontal cortex (29,53,54) of rodents, [ 11 C]Martinostat uptake differences may be more pronounced when comparing controls with medication-free subjects with SCZ/SAD.…”

Gut microbiota manipulation during the prepubertal period shapes behavioral abnormalities in a mouse neurodevelopmental disorder model

“…novel-object recognition (noR) test. NOR test was assessed as previously reported 65,66 . Briefly, mice were given a 10-min acquisition trial and a 5-min recognition trial, separated by a 24 h inter-trial return to their home cage.…”

Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice

“…The injected doses were as follows: DOI, 1 mg/kg; clozapine, 1.5 mg/kg; MK801, 0.5 mg/kg; PCP, 7.5 mg/kg; amphetamine, 6.0 mg/kg and scopolamine, 2 mg/kg. Doses of DOI, and MK801 were selected based on previous studies (Gonzalez-Maeso et al 2007; Fribourg et al 2011; Moreno et al 2011; Kurita et al 2012; Ibi et al 2017). Doses of PCP, amphetamine and scopolamine were selected based on previous studies (Fell et al 2008; Woolley et al 2008; Lavreysen et al 2015), and on pilot dose-response assays (data not shown).…”

“…HSVmGlu2, HSV-mGlu2ΔTM4N, or control HSV-GFP was injected into the frontal cortex by stereotaxic surgery according to standard methods (Kurita et al 2012; Moreno et al 2012; Ibi et al 2017). Mice were anesthetized with a combination of ketamine (100 mg/kg) and xylazine (10 mg/kg) during the surgery.…”

“…More recent findings suggest that clozapine also behaves as a partial agonist activating certain signaling pathways downstream of the 5HT 2A receptor, such as Akt phosphorylation (Schmid et al 2014). Long-lasting exposure to clozapine induces 5-HT 2A receptor internalization in tissue culture (Bhatnagar et al 2001; Raote et al 2013), and down-regulation of frontal cortex 5-HT 2A receptor density in rodent models (Yadav et al 2011; Moreno et al 2013; Ibi et al 2017). These processes of 5-HT 2A receptor internalization and down-regulation after chronic exposure to clozapine treatment have been postulated to be one of the possible mechanisms underlying clozapine’s antipsychotic action.…”