Abstract
Background
Antipsychotic drugs, including both typical such as haloperidol and atypical such as clozapine, were first described in the mid-twentieth century, yet they still remain the current standard of care for schizophrenia. Despite showing relatively tolerable effectiveness in treating hallucinations and delusions, chronic antipsychotic drug exposure leads at present to either persistent or exacerbated cognitive deficits in both clinical studies and preclinical animal models. However, the underlying molecular mechanism of antipsychotics' negative effects on cognition remains enigmatic. Here we identify functional dysregulation of the NF-κB pathway as a principal mediator responsible for deleterious effects of chronic antipsychotic drug treatment along numerous behavioural and physiological traits.
Method
The novel object recognition test was performed to evaluate cognitive function. Synaptic remodeling was analyzed in the mouse brain infected with AAV-eYFP. Synaptic plasticity was evaluated with LTP in the cortical pyramidal neurons.
Result
Chronic treatment with atypical antipsychotics selectively enhanced NF-κB (p65) translocation into the nucleus of pyramidal neurons in mouse frontal cortex; trafficking event that was triggered via serotonin 5-HT2A receptor and MAPK/ERK-dependent down-regulation of expression of the NF-κB repressor IκBα. Such up-regulation of NF-κB activity occurred in association with its increased binding at the promoter region of the Histone deacetylase 2 (Hdac2) gene, thereby augmenting Hdac2 transcription. This paradoxical increase in Hdac2 expression was impeded by either pharmacological or genetic inactivation of NF-κB. Notably, selective deletion of HDAC2 function in forebrain pyramidal neurons prevented the unfavourable effects of chronic antipsychotic treatment on cortical synaptic remodeling and cognitive processes. Conversely, virally mediated activation of cortical pyramidal NF-κB-dependent transcriptional activity minimized the formation of mature spine structures, decreased synaptic plasticity, and exacerbated psychosis-related behaviours and cognitive deficits through a signaling mechanism that required up-regulation of HDAC2.
Conclusion
Our results suggest that activation of the NF-κB pathway by chronic atypical antipsychotic treatment increases HDAC2-dependent negative effects on synaptic plasticity and behavior (Ibi et al., Nat Neurosci 2017). These observations may aid in efforts to develop therapeutic strategies that improve the currently poor outcome in schizophrenia patients.
