Nicotine Alleviate Working Memory Impairment Caused By Schizophrenia Through The Pdlim5/CRTC1 Signaling Pathway In Mice

Cognitive impairment is a core deficit of schizophrenia and current antipsychotic treatments have no or only very limited effects on cognitive impairment.Clinical studies have found that about 50-90%of all psychiatric patients are smokers,and the high rate of smoking may be due to the fact that the patients smoke tobacco to reduce their cognitive symptoms.Nicotine is the key psychoactive component and various studies have reported that nicotine can improve cognition under some circumstances.Therefore,we propose our hypothesis that nicotine alleviates schizophrenia-induced cognitive impairment.Our published results confirmed that nicotine treatment significantly improved rat's working memory in the delayed alternate T maze task?DAT??PMID26263395?.In this current study,MK-801 was applied to induce schizophrenia-like behavior which was confirmed by pre-pulse inhibition?PPI?and T-maze used to assess cognitive performance.Our data showed that MK-801 caused cognitive impairment accompanied by an increase of Pdlim5,an adaptor protein that is critically associated with schizophrenia in medial prefrontal cortex?mPFC?.Of note,chronic nicotine treatment attenuates MK-801-induced schizophrenia-like symptom as well as cognitive impairment by regulating Pdlim5.In addition,nicotine treatment also reduced MK-801-induced decrease of CREB-regulated transcription coactivator1?CRTC1?,a coactivator of CREB which has been shown to play an important role in cognition.More important,MK-801 neither induced schizophrenia-like behavior in Pdlim5^-/-mice,nor decreased CRTC1 in mPFC.In conclusion,our results showed that Chronic nicotine treatment alleviates schizophrenia-induced working memory deficit through regulating Pdlim5 and CRTC1 in mice.