EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling.

Catrina M Loucks,Chunmei Li,Andrea H Mcewan,Laura J Grundy,William Schafer,Michel R Leroux,Denise S Walker,Oliver E Blacque,Tiffany A Timbers,Julie Kennedy,Kwangjin Park,Catharine H Rankin,Jacque-Lynne Johnson,Evan L Ardiel

doi:10.7554/elife.37271

Abstract

Neurons throughout the mammalian brain possess non-motile cilia, organelles with varied functions in sensory physiology and cellular signaling. Yet, the roles of cilia in these neurons are poorly understood. To shed light into their functions, we studied EFHC1, an evolutionarily conserved protein required for motile cilia function and linked to a common form of inherited epilepsy in humans, juvenile myoclonic epilepsy (JME). We demonstrate that C. elegans EFHC-1 functions within specialized non-motile mechanosensory cilia, where it regulates neuronal activation and dopamine signaling. EFHC-1 also localizes at the synapse, where it further modulates dopamine signaling in cooperation with the orthologue of an R-type voltage-gated calcium channel. Our findings unveil a previously undescribed dual-regulation of neuronal excitability at sites of neuronal sensory input (cilium) and neuronal output (synapse). Such a distributed regulatory mechanism may be essential for establishing neuronal activation thresholds under physiological conditions, and when impaired, may represent a novel pathomechanism for epilepsy.

Highlights

Juvenile myoclonic epilepsy (JME) is the most common form of idiopathic epilepsy in humans, making up 10–30% of cases (Delgado-Escueta, 1984)
We generated a GFP reporter of C. elegans EFHC-1 driven by its own promoter, and found that the efhc-1::gfp fusion construct is expressed in a small subset of ciliated mechanosensory neurons: the dopaminergic CEP, ADE and PDE neurons, and the glutamatergic OLQ neurons (Figure 1A)
Despite an established role for EFHC1 in ciliary motility (Conte et al, 2009; Suzuki et al, 2008; Suzuki et al, 2009), its disruption has no effect on ciliary structure (Suzuki et al, 2009), raising the possibility that it plays a role in regulating motility—for example in the mechanosensory feedback required to support normal ciliary motility

Summary

Introduction

Juvenile myoclonic epilepsy (JME) is the most common form of idiopathic epilepsy in humans, making up 10–30% of cases (Delgado-Escueta, 1984). While several neuronal roles have been proposed for EFHC1 (de Nijs et al, 2012; de Nijs et al, 2006; de Nijs et al, 2009; Rossetto et al, 2011; Suzuki et al, 2004), it remains unclear how mutations in EFHC1 lead to epilepsy. EFHC1 is associated with motile cilia that project from specialized cells to enable fluid flow (Conte et al, 2009; Suzuki et al, 2008; Suzuki et al, 2009), but a role for EFHC1 in non-motile cilia that emanate from most cell types to allow for sensory and signaling functions largely remains unexplored (Zhao et al, 2016). There are both motile cilia, which enable cerebrospinal fluid flow, and nonmotile cilia, which project from the cell bodies of all or most neurons (Bishop et al, 2007).

Methods

Results

Conclusion