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

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Antipsychotic medications are standard schizophrenia treatments, but cause cognitive deficits with prolonged use.
• The molecular mechanisms behind antipsychotic-induced cognitive impairment are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying cognitive deficits caused by chronic antipsychotic drug exposure.
• To investigate the role of NF-κB and HDAC2 in antipsychotic-induced cognitive impairment.

Main Methods:

• Studied nuclear translocation of NF-κB in mouse and human frontal cortex after chronic antipsychotic exposure.
• Investigated the effect of NF-κB activity on Hdac2 promoter binding and transcription.
• Examined the impact of HDAC2 deletion and NF-κB activation on synaptic plasticity and cognition in mouse models.

Main Results:

• Chronic antipsychotic exposure increased NF-κB nuclear translocation via 5-HT2A receptor-dependent IκBα downregulation.
• Increased NF-κB activity led to augmented Hdac2 transcription.
• HDAC2 deletion prevented antipsychotic-induced cognitive deficits and synaptic remodeling issues.
• Activated NF-κB signaling decreased cortical synaptic plasticity through HDAC2.

Conclusions:

• NF-κB and HDAC2 are key mediators of antipsychotic-induced cognitive deficits.
• Targeting the NF-κB/HDAC2 pathway could offer novel therapeutic strategies for schizophrenia treatment.
• These findings may help improve cognitive outcomes for schizophrenia patients undergoing antipsychotic therapy.