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Abstract
MK-801, also known as dizocilpine, is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that induces schizophrenia-like symptoms. While astrocytes have been implicated in the pathophysiology of psychiatric disorders, including schizophrenia, astrocytic responses to MK-801 and their significance to schizotypic symptoms are unclear. Changes in the expression levels of glial fibrillary acid protein (GFAP), a marker of astrocyte activation in response to a variety of pathogenic stimuli, were examined in the hippocampus of rats treated with the repeated MK-801 injection (0.5 mg/10ml/kg body weight for 6 days) and in primary cultured hippocampal astrocytes incubated with MK-801 (5 or 20 μM for 24 h). Moreover, the expression levels of BDNF and its receptors TrkB and p75 were examined in MK-801-treated astrocyte cultures. MK-801 treatment enhanced GFAP expression in the rat hippocampus and also increased the levels of GFAP protein and mRNA in hippocampal astrocytes in vitro. Treatment of cultured hippocampal astrocytes with MK-801 enhanced protein and mRNA levels of BDNF, TrkB, and p75. Collectively, our results suggest that hippocampal astrocytes may contribute to the pathophysiology of schizophrenia symptoms associated with NMDA receptor hypofunction by reactive transformation and altered BDNF signaling.
Highlights
Schizophrenia is a chronic and debilitating syndrome that afflicts approximately 1% of the population worldwide [1]
Our results suggest that hippocampal astrocytes may contribute to the pathophysiology of schizophrenia symptoms associated with N-methyl-D-aspartic acid (NMDA) receptor hypofunction by reactive transformation and altered brain-derived neurotrophic factor (BDNF) signaling
glial fibrillary acid protein (GFAP) expression was higher in cultured hippocampal astrocytes after a 24-h treatment with 5 μM MK-801 (P
Summary
Schizophrenia is a chronic and debilitating syndrome that afflicts approximately 1% of the population worldwide [1]. Our previous study indicated that repeated high doses (0.5 mg/kg every day for six days) of MK-801 in rats induced schizophrenia-like behaviors [5]. Astrocytes synthesize and secrete a large number of cytokines that regulate neural plasticity and response to injury, including brain-derived neurotrophic factor (BDNF) [9]. By interacting with p75NTR and TrkB receptors, BDNF facilitate long-term depression (LTD) and long-term potentiation (LTP), respectively, two forms of synaptic plasticity implicated in hippocampus-dependent learning [14]. Deficits in these synaptoplastic processes could underlie some of the cognitive deficits exhibited by schizophrenia patients. In the current study, we evaluated GFAP, BDNF, TrkB, and p75 expression levels in hippocampal astrocytes in the animal model of schizophrenia based on the repeated treatment with MK-801 and/or in primary cultures of hippocampal astrocytes
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