Small-molecule TrkB agonist 7,8-dihydroxyflavone reverses cognitive and synaptic plasticity deficits in a rat model of schizophrenia

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Abstract

Cognitive deficits are the core symptoms of schizophrenia and major contributors to disability in schizophrenic patients, but effective treatments are still lacking. Previous studies have demonstrated that impaired BDNF/TrkB signaling is associated with the cognitive impairments of schizophrenia. 7,8-Dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood–brain barrier after oral or intraperitoneal administration. The present study aimed to assess the effect of 7,8-DHF on the cognitive and synaptic impairments of schizophrenia. A brief disruption of NMDA receptors with MK-801 during early development serves as an animal model for cognitive deficits of schizophrenia. We found that MK-801-treated rats showed significant deficits in working learning ability and hippocampal synaptic plasticity, as well as reduction of BDNF, TrkB, and phosphorylated TrkB in the hippocampus. After intraperitoneal administration with 7,8-DHF (5 mg/kg) once daily for a consecutive 14 days, we found that chronic 7,8-DHF treatment significantly enhanced the activation of phosphorylated TrkB at the Y515 and Y816 sites, increased the phosphorylation levels of TrkB downstream signal cascades including ERK1/2, CaMKII, CREB and GluR1, and promoted hippocampal synaptic plasticity, which in turn rescued performance in spatial working learning. Our results thus demonstrate that activation of TrkB signaling can reverse the cognitive deficits of schizophrenia and strongly suggest a potential usefulness for 7,8-DHF or a TrkB agonist in treating schizophrenia-related cognitive impairments.

Graphical abstract

7,8-DHF restores the learning ability of MK-801-treated rats in Morris water maze task. MK-801-treated rats receive daily intraperitoneal injection of either 7,8-DHF (5 mg/kg) or vehicle (DMSO) for 14 consecutive days. Saline-treated rats also received injection with the same volume of vehicle. Each rat was subjected to four trails daily for five consecutive days. (A) The escape latency to reach the hidden platform over the five testing days. (B) The mean path length to reach the hidden platform over the five testing days. (C) Swimming velocity in the hidden platform test. (D) The latency to locate a visible platform at test on day 6. Each datum represents the mean ± S.E.M. for 12 animals.

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