Splice variants of the CaV1.3 L-type calcium channel regulate dendritic spine morphology.

Ruslan Stanika,Marta Campiglio,Jörg Striessnig,Alexandra Pinggera,Amy Lee,Gerald J Obermair,Bernhard E Flucher

doi:10.1038/srep34528

Ruslan Stanika, Marta Campiglio + Show 5 more

Open Access

https://doi.org/10.1038/srep34528

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Abstract

Dendritic spines are the postsynaptic compartments of glutamatergic synapses in the brain. Their number and shape are subject to change in synaptic plasticity and neurological disorders including autism spectrum disorders and Parkinson’s disease. The L-type calcium channel CaV1.3 constitutes an important calcium entry pathway implicated in the regulation of spine morphology. Here we investigated the importance of full-length CaV1.3L and two C-terminally truncated splice variants (CaV1.342A and CaV1.343S) and their modulation by densin-180 and shank1b for the morphology of dendritic spines of cultured hippocampal neurons. Live-cell immunofluorescence and super-resolution microscopy of epitope-tagged CaV1.3L revealed its localization at the base-, neck-, and head-region of dendritic spines. Expression of the short splice variants or deletion of the C-terminal PDZ-binding motif in CaV1.3L induced aberrant dendritic spine elongation. Similar morphological alterations were induced by co-expression of densin-180 or shank1b with CaV1.3L and correlated with increased CaV1.3 currents and dendritic calcium signals in transfected neurons. Together, our findings suggest a key role of CaV1.3 in regulating dendritic spine structure. Under physiological conditions it may contribute to the structural plasticity of glutamatergic synapses. Conversely, altered regulation of CaV1.3 channels may provide an important mechanism in the development of postsynaptic aberrations associated with neurodegenerative disorders.

Highlights

Dendritic spines are the postsynaptic compartments of glutamatergic synapses in the brain
Our experiments demonstrate that expression of the short CaV1.3 splices or increased levels of densin-180 or shank1b co-expressed with full-length CaV1.3 induce aberrant dendritic spine elongation, which correlates with increased CaV1.3 currents in cultured hippocampal neurons
It is important to note that in our experiments in hippocampal neurons calcium channel α1 subunits are expressed without the ectopic expression of additional auxiliary subunits

Summary

Introduction

Dendritic spines are the postsynaptic compartments of glutamatergic synapses in the brain Their number and shape are subject to change in synaptic plasticity and neurological disorders including autism spectrum disorders and Parkinson’s disease. The primary postsynaptic compartments of glutamatergic synapses in neurons of the central nervous system (CNS), play a key role in the manifestation of neuronal plasticity and in memory formation. It is not surprising that disorders of the CNS, such as autism spectrum disorders (ASD), schizophrenia, intellectual disabilities, as well as neurodegenerative diseases including Alzheimer’s or Parkinson’s, go hand in hand with changes in the number and morphology of dendritic spines and altered synaptic structure[1]. Most importantly CaV1.3 channels have been associated with altered dendritic spine morphology in animal models of dopamine depletion, which induce a PD-like phenotype Have been linked to ASDs23,24 and to a severe congenital multiorgan syndrome with primary aldosteronism, seizures, and neurologic abnormalities[25,26]

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