Emerging Roles of Activity-Dependent Alternative Splicing in Homeostatic Plasticity

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.

Keywords: P/Q-type Ca2+ channels; alternative splicing; homeostatic plasticity; homer1; repressor element 1 silencing transcription factor (REST).

Figure 1

Genes to function in homeostatic plasticity.

Figure 2

Activity-dependent alternative splicing in homeostatic plasticity. (A) A chronic increase in neuronal activity downregulates the expression of the splicing factor nSR100, with consequent skipping of a 16-nt-long microexon in the pre-mRNA of the transcriptional repressor REST (repressor element 1 silencing transcription factor). The resulting REST protein is active and reduces the expression of Na_V1.2 and of presynaptic proteins. These two effects contribute to homeostatic intrinsic plasticity and presynaptic homeostatic plasticity, respectively. (*) Indicates a STOP codon. (B) The selective induction of the short isoform Homer1a upon increase in neuronal activity is mediated by the transcription factor myocyte enhancer factor 2 (MEF2), which promotes expression of the Homer1 gene, and by a concomitant termination of transcription between exons 5 and 6. Homer1a outcompetes the longer isoforms of Homer1, resulting in dispersion of group 1 mGluRs and dephosphorylation of AMPARs. This contributes to synaptic downscaling. (C) Mutually exclusive splicing of P/Q-type Ca²⁺ channels in presynaptic homeostatic plasticity. (Ca) Structural model of human Ca_V2.1[EFb] (UniProt ID: O00555; Martinez-Ortiz and Cardozo, 2018), highlighting the full C-terminus (green, cyan, blue), the part of the EF-hand-like domain shared between Ca_V2.1[EFa] and Ca_V2.1[EFb] (E helix; cyan) and the sequence specific to Ca_V2.1[EFb] (loop, F helix and downstream residues; blue). (Cb) Phylogenetic tree of human Ca_V1 and Ca_V2 channels and of Cacophony and DmCa1D from Drosophila melanogaster for the amino acidic region corresponding to exons 37 of Ca_V2.1 (Clustal Omega www.ebi.ac.uk/Tools/msa/clustalo/, rendering using TreeDyb, http://www.phylogeny.fr/one_task.cgi?tasktype=treedyn, Chevenet et al., 2006); UniProt IDs: Ca_V1.1: Q13698, aa: 1414–1446; Ca_V1.2: Q13936, aa: 1587–1589; Ca_V1.3: Q01668, aa: 1497–1529; Ca_V1.4: O60840, aa: 1474–1506; Ca_V2.1b: O00555, aa: 1843–1875; Ca_V2.2b: Q00975, aa: 1741–1773; Ca_V2.3b: Q15878, aa: 1756–1788; Ca_V2.1a: O00555-4, aa: 1844–1876; Cacophony: P1645, aa: 1370–1402; DmCa1D: Q24270, aa: 1959–1991; sequences for Ca_V2.2a and Ca_V2.3a are as in Thalhammer et al. (2017). The three exons 37a cluster together as do the three exons 37b, suggesting conservation of these mutually exclusive exons across Ca_V2 channels; the corresponding region of Cacophony from D. melanogaster is more tightly related to exon 37b. (Cc) The increased expression of the isoform Ca_V2.1[EFa] upon chronic activity deprivation might occur following demethylation of the exon 37a locus with consequent binding of the chromatin organizer CCCTC-binding factor (CTCF) to it. Ca_V2.1[EFa] localizes in close proximity to fuse-competent synaptic vesicles, thereby supporting effectively vesicle release and presynaptic homeostatic plasticity. Drawing of relative exon/intron length is to scale only in (Cc); numbers of mRNAs and proteins are not intended to be quantitative.