Abstract
Dizocilpine (MK-801), a non-competitive N-methyl-D-aspartic acid receptor (NMDA-R) antagonist, can induce schizophrenia-like symptoms in healthy individuals, implicating NMDA-R hypofunction in disease pathogenesis. Brain-derived neurotrophic factor (BDNF) is also implicated in schizophrenia, and expression is regulated by NMDA-R activity, suggesting a functional link. We previously found that BDNF signaling was upregulated by MK-801 in cultured hippocampal astrocytes, but the underlying mechanism is not clear. To address this issue, the levels of BDNF expression and secretion were evaluated in hippocampal astrocytes incubated with MK-801 by ELISA and qPCR, with and without NMDA co-incubation or pretreatment of either the ERK1/2 inhibitor, PD98059 or the PI3K inhibitor, LY294002. The apoptosis, viability, and proliferation of the astrocytes were also examined. In the current study, we demonstrate that MK-801 treatment (20 μM for 5 days) enhances the proliferation of rat cultured hippocampal astrocytes. Expression of BDNF mRNA was enhanced after 24 h in MK-801, but returned to near baseline over the next 24 h in the continued presence of MK-801. However, two successive 24-h treatments enhanced BDNF expression. These application regimens had no effect on apoptosis or proliferation rate. Co-addition of NMDA significantly inhibited MK-801-induced upregulation of BDNF. Similarly, MK-801-induced BDNF upregulation was blocked by pretreatment with inhibitors of PI3K and ERK1/2, but not by inhibitors of p38 and JNK. These findings suggested that astrocytes may contribute to the acute neurological and behavioral response to MK-801 treatment via a transient increase in BDNF expression involving NMDA-R–PI3K–ERK signaling.
Highlights
Astrocytes are the most abundant type of glial cell in the central nervous system, and crucial for neuroplasticity and neural homeostasis across life-span to modulate metabolic exchange by various secreted and contact-mediated signals (Clarke and Barres, 2013; Araque et al, 2014)
It is widely known that NMDARs activate primary signaling cascades including PI3K and ERK signaling pathways, both of which are involved in the pathogenesis of schizophrenia and the therapeutic mechanisms of antipsychotic agents (Seo et al, 2007)
PI3K is an essential upstream regulator of ERK activation, and it has been reported that the activation of ERK stimulated by NMDA receptor is completely or partially dependent on PI3K activity (Opazo et al, 2003).the current study was designed to assess the contributions of various N-methyl-D-aspartic acid receptor (NMDA-R)-linked signaling pathways to MK-801-induced upregulation of astrocytic Brain-derived neurotrophic factor (BDNF) expression and release
Summary
Astrocytes are the most abundant type of glial cell in the central nervous system, and crucial for neuroplasticity and neural homeostasis across life-span to modulate metabolic exchange by various secreted and contact-mediated signals (Clarke and Barres, 2013; Araque et al, 2014). BDNF is the most abundant neurotrophin in the brain, with high expression in the hippocampus, prefrontal cortex (PFC), and hypothalamus, where it supports a variety of functions, such as the regulation of neuronal morphology and synaptic plasticity (Han and Deng, 2018; De Vincenti et al, 2019). It is widely known that NMDARs activate primary signaling cascades including PI3K and ERK signaling pathways, both of which are involved in the pathogenesis of schizophrenia and the therapeutic mechanisms of antipsychotic agents (Seo et al, 2007). PI3K is an essential upstream regulator of ERK activation, and it has been reported that the activation of ERK stimulated by NMDA receptor is completely or partially dependent on PI3K activity (Opazo et al, 2003).the current study was designed to assess the contributions of various NMDA-R-linked signaling pathways to MK-801-induced upregulation of astrocytic BDNF expression and release
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