Flavonoid fisetin reverses impaired hippocampal synaptic plasticity and cognitive function by regulating the function of AMPARs in a male rat model of schizophrenia

• Published in: Journal of neurochemistry 2021-07, Vol.158 (2), p.413-428
• Main Authors: Zhan, Jin‐Qiong, Chen, Chun‐Nuan, Wu, Si‐Xian, Wu, Han‐Jun, Zou, Ke, Xiong, Jian‐Wen, Wei, Bo, Yang, Yuan‐Jian
• Format: Article
• Language: English
• Subjects: AMPA receptor; Animal diseases; Animals; Ca2+/calmodulin-dependent protein kinase II; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calmodulin; Cognition; Cognition - drug effects; Cognitive ability; cognitive deficits; Cognitive tasks; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - drug effects; Cyclic AMP Response Element-Binding Protein - metabolism; Dizocilpine; Dizocilpine Maleate - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Extracellular signal-regulated kinase; Fear; Fear - drug effects; Fear - psychology; Fear conditioning; fisetin; Flavonoids; Flavonols - pharmacology; Glutamic acid receptors; Hippocampal plasticity; Hippocampus; Injections, Intraperitoneal; Kinases; Long-term potentiation; Male; Males; MAP Kinase Signaling System - drug effects; Maze Learning - drug effects; Memory; Mental disorders; N-Methyl-D-aspartic acid receptors; Neurological diseases; Neuronal Plasticity - drug effects; Phosphorylation; Plasticity; Propionic acid; Proteins; Psychomotor Performance - drug effects; Rats; Rats, Sprague-Dawley; Receptors; Receptors, AMPA - drug effects; Rodents; Schizophrenia; Schizophrenia - drug therapy; Schizophrenic Psychology; Spatial memory; Synapses - drug effects; synaptic plasticity; Western blotting; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15370

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. 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‐associat