Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects.
Nat Neurosci
; 20(9): 1247-1259, 2017 Sep.
Article
in En
| MEDLINE
| ID: mdl-28783139
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.
Full text:
1
Database:
MEDLINE
Main subject:
Synapses
/
Antipsychotic Agents
/
NF-kappa B
/
Cognition Disorders
/
Histone Deacetylase 2
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Year:
2017
Type:
Article