Experience- and diet-dependent regulation of synaptic plasticity can underlie beneficial effects of active lifestyle on the aging brain. Our previous results demonstrate a key role for brain-derived neurotrophic factor (BDNF) and MSK1 kinase in experience-related homeostatic synaptic scaling. Astroglia has been recently shown to release BDNF via a calcium-dependent mechanism. To elucidate a role for astroglia-derived BDNF in homeostatic synaptic plasticity in the aging brain, we explored the experience- and diet-related alterations of synaptic transmission and plasticity in transgenic mice with impairment of the BDNF/MSK1 pathway (MSK1 kinase dead knock-in mice, MSK1 KD) and impairment of glial exocytosis (dnSNARE mice). We found that prolonged tonic activation of astrocytes caused BDNF-dependent increase in the efficacy of excitatory synapses accompanied by enlargement of synaptic boutons. We also observed that exposure to environmental enrichment (EE) and caloric restriction (CR) enhanced the Ca²⁺ signalling in cortical astrocytes and strongly up-regulated the excitatory and down-regulated inhibitory synaptic currents in old wild-type mice, thus counterbalancing the impact of ageing on astroglial and synaptic signalling. The EE- and CR-induced up-scaling of excitatory synaptic transmission in neocortex was accompanied by the enhancement of long-term synaptic potentiation. Importantly, effects of EE and CR on synaptic transmission and plasticity was significantly reduced in the MSK1 KD and dnSNARE mice. Combined, our results suggest that astroglial release of BDNF is important for the homeostatic regulation of cortical synapses and beneficial effects of EE and CR on synaptic transmission and plasticity in aging brain.

中文翻译：

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星形胶质细胞衍生的 BDNF 和 MSK-1 介导经验和饮食依赖性突触可塑性。

突触可塑性的经验和饮食依赖性调节是积极生活方式对衰老大脑有益影响的基础。我们之前的研究结果证明了脑源性神经营养因子 (BDNF) 和 MSK1 激酶在与体验相关的稳态突触缩放中的关键作用。最近显示星形胶质细胞通过钙依赖性机制释放 BDNF。为了阐明星形胶质细胞衍生的 BDNF 在衰老大脑稳态突触可塑性中的作用，我们探讨了 BDNF/MSK1 通路受损的转基因小鼠（MSK1 激酶死亡敲除）突触传递和可塑性的经验和饮食相关改变。在小鼠中，MSK1 KD）和神经胶质胞吐作用受损（dnSNARE 小鼠）。我们发现，星形胶质细胞的长期强直激活导致兴奋性突触功效的 BDNF 依赖性增加，同时伴随着突触小结的扩大。我们还观察到暴露于环境富集 (EE) 和热量限制 (CR) 会增强 Ca^{皮质星形胶质细胞中的2+}信号传导并强烈上调老年野生型小鼠的兴奋性和下调抑制性突触电流，从而抵消衰老对星形胶质细胞和突触信号传导的影响。EE 和 CR 诱导的新皮质中兴奋性突触传递的放大伴随着长期突触增强的增强。重要的是，在 MSK1 KD 和 dnSNARE 小鼠中，EE 和 CR 对突触传递和可塑性的影响显着降低。综上所述，我们的研究结果表明，BDNF 的星形胶质细胞释放对于皮质突触的稳态调节以及 EE 和 CR 对衰老大脑的突触传递和可塑性的有益作用很重要。