Abstract
MK-801, also known as dizocilpine, is a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that induces schizophrenia-like symptoms. Our previous study showed that brain-derived neurotrophic factor (BDNF) signaling was upregulated in cultured hippocampal astrocytes in response to MK-801. However, dysfunctional NMDA receptors are mainly expressed in neurons. The effects of MK-801 on neuron-derived BDNF expression and of risperidone on MK-801-induced cognitive impairment and changes in BDNF expression are unclear. To address this issue, we examined BDNF expression in the hippocampus of rats that received repeated injections of MK-801 (0.5 mg/kg body weight for 6 days) and in primary cultured hippocampal neurons incubated with 20 μM MK-801 for 24 h. BDNF expression and cognitive function were also evaluated in rats receiving intraperitoneal injections of risperidone (1 mg/kg body weight) once daily for 7 days and in hippocampal neurons incubated with 10 μM risperidone following MK801 treatment. MK-801 treatment decreased BDNF expression in the rat hippocampus as well as the expression and secretion of BDNF in hippocampal neurons in vitro. However, risperidone reversed the effects of MK801 on BDNF level and improved cognitive function in rats treated with MK801. These findings suggest that risperidone may alleviate cognitive impairment caused by MK801 via upregulation of BNDF signaling in the hippocampus.
Highlights
Schizophrenia is a chronic and debilitating syndrome with an onset in adolescence and young adulthood followed by a chronic course, episodic aggravation, and often unfavorable outcome that affects approximately 1% of the population worldwide (Capuano et al, 2002; Jobe and Harrow, 2005)
Brain-derived neurotrophic factor (BDNF) transcript level was reduced to 74% of the control by 20 μM MK-801 treatment for 2 h (F = 9.560, df1 = 3, df2 = 8, P = 0.005), and was restored to about 95% of the control after 10 μM risperidone treatment for 24 h, which was higher than the level in the MK801 group (P = 0.021; Figure 2A; Supplementary Table S7)
BDNF concentration in culture supernatant was reduced to 36.0 ± 2.0 for neurons treated with 20 μM MK-801 for 2 h (F = 4.387, df1 = 3, df2 = 8, P = 0.042), as determined by Enzyme-Linked Immunosorbent Assay (ELISA)
Summary
Schizophrenia is a chronic and debilitating syndrome with an onset in adolescence and young adulthood followed by a chronic course, episodic aggravation, and often unfavorable outcome that affects approximately 1% of the population worldwide (Capuano et al, 2002; Jobe and Harrow, 2005). By binding to TrkB and p75 neurotrophin (p75NTR) receptors, BDNF mediates long-term potentiation (LTP) and long-term depression (LTD), respectively, which are two forms of synaptic plasticity that represent cellular correlates of learning and memory in the hippocampus (Lu and Martinowich, 2008). Deficits in these processes may underlie some of the cognitive deficits exhibited by schizophrenia patients. Many studies have suggested that BDNF plays an important role in the pathophysiology of schizophrenia (Lu and Martinowich, 2008; Zhang et al, 2012). It is thought that antipsychotics differentially affect serum or plasma BDNF protein levels according to the ethnic background of patients with schizophrenia (Huang, 2013)
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