Editors' ChoiceNeuroscience

Protecting cognition from antipsychotics

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Science Signaling  26 Sep 2017:
Vol. 10, Issue 498, eaap9121
DOI: 10.1126/scisignal.aap9121

Inhibiting a mechanism that mediates cognitive deficits caused by antipsychotic drugs may improve clinical outcomes for schizophrenia patients.

Antipsychotic drugs help to reduce the symptoms (such as hallucinations and delusions) associated with schizophrenia, but they also impair cognitive ability in patients such that everyday activities may become difficult. In both mice and postmortem brain tissue from patients, Ibi et al. found that chronic antipsychotic exposure increased the amount of the transcription factor nuclear factor κB (NF-κB) in the nucleus of neurons in the frontal cortex. The antipsychotic clozapine decreases the density of serotonin 5-HT2A receptors, which consequently decreased transcription of the gene encoding the NF-κB repressor inhibitor of κBα (IκBα). Nuclear NF-κB subsequently increased the expression of a target gene encoding the histone deacetylase HDAC2, which decreased the acetylation and expression of genes encoding proteins involved in cell morphogenesis, neuron projection, and synapse structure, features that are critical for synaptic function and cognition. Prolonged antipsychotic treatment or viral vector–mediated expression of activated NF-κB altered synaptic structure and function and impaired performance during memory tasks in wild-type mice but not Hdac2–/– mice or mice expressing a constitutively active form of IκBα. These findings identify targets for therapeutic development that may improve the quality of life for schizophrenia patients.

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