Emerging Roles of Activity-Dependent Alternative Splicing in Homeostatic Plasticity.

Agnes Thalhammer,Lorenzo A Cingolani,Fanny Jaudon

doi:10.3389/fncel.2020.00104

Abstract

Homeostatic plasticity refers to the ability of neuronal networks to stabilize their activity in the face of external perturbations. Most forms of homeostatic plasticity ultimately depend on changes in the expression or activity of ion channels and synaptic proteins, which may occur at the gene, transcript, or protein level. The most extensively investigated homeostatic mechanisms entail adaptations in protein function or localization following activity-dependent posttranslational modifications. Numerous studies have also highlighted how homeostatic plasticity can be achieved by adjusting local protein translation at synapses or transcription of specific genes in the nucleus. In comparison, little attention has been devoted to whether and how alternative splicing (AS) of pre-mRNAs underlies some forms of homeostatic plasticity. AS not only expands proteome diversity but also contributes to the spatiotemporal dynamics of mRNA transcripts. Prominent in the brain where it can be regulated by neuronal activity, it is a flexible process, tightly controlled by a multitude of factors. Given its extensive use and versatility in optimizing the function of ion channels and synaptic proteins, we argue that AS is ideally suited to achieve homeostatic control of neuronal output. We support this thesis by reviewing emerging evidence linking AS to various forms of homeostatic plasticity: homeostatic intrinsic plasticity, synaptic scaling, and presynaptic homeostatic plasticity. Further, we highlight the relevance of this connection for brain pathologies.

Highlights

FROM GENES TO FUNCTIONOver the last two decades, a vast array of homeostatic plasticity adaptations, which enable neuronal networks to stabilize their activity in the face of external perturbations, have been identified
These involve adjustments in synaptic strength by means of preand postsynaptic mechanisms and in intrinsic excitability. Both synaptic and intrinsic forms of homeostatic plasticity depend on changes in expression or activity of ion channels and synaptic proteins, which may occur at the gene, transcript, or protein level (Figure 1)
Because this isoform is the more efficient of the two in driving vesicle release, its higher expression levels appear perfectly suited to counteract the decrease in network activity (Figure 2Cc; Thalhammer et al, 2017). These findings provide a precise molecular basis for the involvement of P/Q-type Ca2+ channels in presynaptic homeostatic plasticity (Frank et al, 2006; Jakawich et al, 2010; Lazarevic et al, 2011; Zhao et al, 2011; Jeans et al, 2017) and highlight the importance of activity-dependent alternative splicing (AS) in homeostatic synaptic plasticity. It is not known how network activity regulates this splicing event, it has recently been proposed that inclusion of exon 37a or 37b in CaV2.2 is consequent to differences in chromatin structure and transcription rates, rather than being directly regulated at the mRNA level (Javier et al, 2019; Lopez Soto and Lipscombe, 2020)

Summary

Introduction

FROM GENES TO FUNCTIONOver the last two decades, a vast array of homeostatic plasticity adaptations, which enable neuronal networks to stabilize their activity in the face of external perturbations, have been identified. Most forms of homeostatic plasticity depend on changes in the expression or activity of ion channels and synaptic proteins, which may occur at the gene, transcript, or protein level.

Results

Conclusion