Lalo Ulyana, Bogdanov Alexander, Moss Guy W, Pankratov Yuriy
School of Life Sciences, University of Warwick, Gibbet Hill Campus, Coventry CV4 7AL, UK.
School of Life Sciences, Immanuel Kant Baltic Federal University, 2 Universitetskaya str., Kaliningrad 236040, Russia.
Brain Sci. 2020 Jul 18;10(7):462. doi: 10.3390/brainsci10070462.
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 Ca 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.
经验和饮食依赖的突触可塑性调节可能是积极生活方式对衰老大脑产生有益影响的基础。我们之前的研究结果表明，脑源性神经营养因子（BDNF）和MSK1激酶在与经验相关的稳态突触缩放中起关键作用。最近有研究表明，星形胶质细胞可通过钙依赖机制释放BDNF。为了阐明星形胶质细胞源性BDNF在衰老大脑稳态突触可塑性中的作用，我们研究了BDNF/MSK1途径受损的转基因小鼠（MSK1激酶失活敲入小鼠，MSK1 KD）和胶质细胞胞吐作用受损的小鼠（dnSNARE小鼠）中与经验和饮食相关的突触传递和可塑性变化。我们发现，星形胶质细胞的长期强直激活会导致BDNF依赖的兴奋性突触效能增加，并伴有突触小体增大。我们还观察到，环境富集（EE）和热量限制（CR）可增强老年野生型小鼠皮质星形胶质细胞的钙信号，并强烈上调兴奋性突触电流，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的影响。EE和CR诱导的新皮质兴奋性突触传递上调与长期突触增强的增强有关。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著降低。综合来看，我们的结果表明，星形胶质细胞释放BDNF对皮质突触的稳态调节以及EE和CR对衰老大脑突触传递和可塑性的有益影响至关重要。
