The astrocytic transporter SLC7A10 (Asc-1) mediates glycinergic inhibition of spinal cord motor neurons.

Jeffrey T Ehmsen,Yue Wang,Sascha Du Lac,Anna E Johnson,Jeffrey D Rothstein,Nikhil Paladugu,Mark P Mattson,Yong Liu,Ahmet Höke

doi:10.1038/srep35592

Abstract

SLC7A10 (Asc-1) is a sodium-independent amino acid transporter known to facilitate transport of a number of amino acids including glycine, L-serine, L-alanine, and L-cysteine, as well as their D-enantiomers. It has been described as a neuronal transporter with a primary role related to modulation of excitatory glutamatergic neurotransmission. We find that SLC7A10 is substantially enriched in a subset of astrocytes of the caudal brain and spinal cord in a distribution corresponding with high densities of glycinergic inhibitory synapses. Accordingly, we find that spinal cord glycine levels are significantly reduced in Slc7a10-null mice and spontaneous glycinergic postsynaptic currents in motor neurons show substantially diminished amplitudes, demonstrating an essential role for SLC7A10 in glycinergic inhibitory function in the central nervous system. These observations establish the etiology of sustained myoclonus (sudden involuntary muscle movements) and early postnatal lethality characteristic of Slc7a10-null mice, and implicate SLC7A10 as a candidate gene and auto-antibody target in human hyperekplexia and stiff person syndrome, respectively.

Highlights

Motor neuron activity is tonically regulated by inhibitory currents, mediated through spontaneous and evoked synaptic release of glycine and GABA
We show that SLC7A10 is substantially enriched in a subset of astrocytes, in contrast to previous reports of exclusive neuronal expression, and specify a primary role for this transporter in maintaining presynaptic neuronal glycine stores required for glycinergic inhibitory function
SLC7A10 expression parallels the expression of glycinergic transporter 2 (GLYT2) (SLC6A5), a pre-synaptic glycine transporter highly enriched in glycinergic inhibitory neurons and considered a marker for these neurons (Fig. 1c–h), and gephyrin (GPHN), a post-synaptic glycine/GABAA receptor clustering protein (Fig. 1i–n)

Summary

Introduction

Motor neuron activity is tonically regulated by inhibitory currents, mediated through spontaneous and evoked synaptic release of glycine and GABA. GLYT2 deficiency, in contrast, is associated with hypertonia, ataxia, exaggerated startle responses called hyperekplexia, and early postnatal lethality; this is thought to reflect impaired reuptake of vesicular glycine into glycinergic neurons following glycine release (presynaptic recycling), leading to insufficient inhibitory activity[3,4]. (sudden involuntary muscle movements)[6]; median lifespan is 21 days This phenotype has been believed to reflect neuronal hyperexcitability arising from impaired transport of the NMDAR co-agonist D-serine[6]. We show that SLC7A10 is substantially enriched in a subset of astrocytes, in contrast to previous reports of exclusive neuronal expression, and specify a primary role for this transporter in maintaining presynaptic neuronal glycine stores required for glycinergic inhibitory function

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Conclusion