Flavonoid fisetin reverses impaired hippocampal synaptic plasticity and cognitive function by regulating the function of AMPARs in a male rat model of schizophrenia. Issue 2 (12th May 2021)

• Record Type: Journal Article
• Authors: Zhan, Jin‐Qiong; Chen, Chun‐Nuan; Wu, Si‐Xian; Wu, Han‐Jun; Zou, Ke; Xiong, Jian‐Wen; Wei, Bo; Yang, Yuan‐Jian
• Is Part Of: Journal of neurochemistry. Volume 158:Issue 2(2021)
• Page Start: 413
• Page End: 428
• Publication Date: 2021-05-12
• Subjects: AMPA receptor -- cognitive deficits -- fisetin -- schizophrenia -- synaptic plasticity; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15370
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Cognitive deficits are the core feature of schizophrenia and effective treatment strategies are still missing. Previous studies have reported that fisetin promotes long‐term potentiation (LTP) and cognitive function in normal rodents and other model animals of neurological diseases. The aim of this study was to assess the effect of fisetin on synaptic plasticity and cognitive deficits caused by a brief disruption of N‐methyl‐D‐aspartate receptors (NMDARs) with dizocilpine (MK‐801) during early development in rats. The cognitive performance was examined by the Morris water maze task and a fear conditioning test. Hippocampal synaptic plasticity was investigated by field potential recording. The expression of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors (AMPARs) and cognition‐related proteins was measured by western blotting. We found that intraperitoneal administration of fisetin rescued hippocampus‐dependent spatial and contextual fear memory in MK‐801 rats. In parallel with these behavioral results, fisetin treatment in MK‐801 rats reversed the impairment of hippocampal LTP. At the molecular level, fisetin treatment selectively increased the phosphorylation and surface expression of AMPA receptor subunit 1 (GluA1) in MK‐801‐treated rats. Moreover, fisetin restored the phosphorylation levels of calcium‐calmodulin‐dependent kinaseII (CaMKII), cAMP response element‐binding protein (CREB), and the extracellular signal‐regulated kinase (ERK1/2) in MK‐801‐treated rats. Collectively, our findings demonstrate that fisetin treatment can reverse the deficits of hippocampal synaptic plasticity and memory in a male rat model of schizophrenia by restoring the phosphorylation and surface expression of AMPAR GluA1 subunit, suggesting fisetin as a promising therapeutic candidate for schizophrenia‐associated cognitive deficits. Abstract : Cognitive deficits are the core features of schizophrenia. Dizocilpine (MK‐801)‐treated rats were used as an animal model of schizophrenia in this study. We showed that chronic fisetin treatment in MK‐801 rats selectively increased the phosphorylation and surface expression of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptor subunit 1 (GluA1) in the hippocampus, in turn to reverse the impairment of long‐term potentiation (LTP) as well as the hippocampus‐dependent spatial and contextual fear memory deficits. These results suggest that fisetin might be a promising therapeutic candidate for schizophrenia‐associated cognitive deficits.