Role for Astroglia-Derived BDNF and MSK1 in Homeostatic Synaptic Plasticity

Ulyana Lalo,Yuriy Pankratov,Guy W J Moss,Bruno G Frenguelli,Alexander Bogdanov

doi:10.3390/neuroglia1020026

Abstract

Homeostatic scaling of synaptic strength in response to environmental stimuli may underlie the beneficial effects of an active lifestyle on brain function. Our previous results highlighted a key role for brain-derived neurotrophic factor (BDNF) and mitogen- and stress-activated protein kinase 1 (MSK1) in experience-related homeostatic synaptic plasticity. Astroglia have recently been shown to serve as an important source of BDNF. To elucidate a role for astroglia-derived BDNF, we explored homeostatic synaptic plasticity in transgenic mice with an impairment in the BDNF/MSK1 pathway (MSK1 kinase dead knock-in (KD) mice) and impairment of glial exocytosis (dnSNARE mice). We observed that prolonged tonic activation of astrocytes caused BDNF-dependent upregulation of excitatory synaptic currents accompanied by enlargement of synaptic boutons. We found that exposure to environmental enrichment (EE) and caloric restriction (CR) strongly upregulated excitatory but downregulated inhibitory synaptic currents in old wild-type mice, thus counterbalancing the impact of ageing on synaptic transmission. In parallel, EE and CR enhanced astrocytic Ca2+-signalling. Importantly, we observed a significant deficit in the effects of EE and CR on synaptic transmission in the MSK1 KD and dnSNARE mice. Combined, our results strongly support the importance of astrocytic exocytosis of BDNF for the beneficial effects of EE and CR on synaptic transmission and plasticity in the ageing brain.

Highlights

The ability of neurons to autonomously scale their synaptic strength in response to hyper- or hypoexcitability of their neighbours is instrumental for brain adaptation to environmental challenges during development, adulthood, and ageing [1,2,3]
Our experiments in cultured neurons demonstrated that long-term enhancement of astrocytic Ca2+-signalling can lead to neuronal synaptic scaling that engages the same Brain-derived neurotrophic factor (BDNF)/mitogen- and stress-activated protein kinase 1 (MSK1) cascade that has been shown to underlie homeostatic synaptic plasticity induced by alterations in neuronal firing [9,10]
Combined with recently reported data unequivocally showing the ability of astrocytes to release BDNF via exocytosis [14], our results strongly suggest that astrocyte-derived BDNF can modulate homeostatic synaptic scaling

Summary

Introduction

The ability of neurons to autonomously scale their synaptic strength in response to hyper- or hypoexcitability of their neighbours is instrumental for brain adaptation to environmental challenges during development, adulthood, and ageing [1,2,3]. Such forms of adaptive changes in synaptic strength are generally termed homeostatic synaptic plasticity [2]. Since the release of BDNF can be increased by various environmental stimuli, such as physical activity or a change in diet [9,12,13], the BDNF/MSK1 pathway might play an important role in the beneficial effects of both physical activity and caloric restriction (CR) on synaptic function, in particular in the ageing brain

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Results

Conclusion