Extrasynaptic GlyR a1 subunits regulate startle response in a cell-type specific mechanism

Authors

  • S Wei
  • HL Pan
  • Y XU
  • DM Lovinger
  • L Zhang

Abstract

Glycine receptor a1 (GlyRa1) subunits are the most abundant inhibitory ligand-gated ion channels expressed in spinal cord and brainstem at the adult stage. Global GlyRa1 deficiency disrupts glycinergic synaptic transmission and causes exaggerated startle response in human and animals. However, little is known about the in vivo impact of extrasynaptic GlyRa1 receptors. To address it, we selectively depleted GlyRa1 subunits from GlyT2Cre;Glra1flox/flox mice (GlKO) and inducible CamK2aCreER;Glra1flox/flox (CaKO) mice. The mRNA signals of GLYT2, CAMK2A and GLRA1 are colocalized in spinal cord and brainstem of WT mice, while deletion of GlyRa1 from GlyT2+ and CamK2a+ neurons reduced the levels of GlyRa1 protein,. Both homozygous and heterozygous GlKO mice displayed a decreased level of startle response to acoustic stimuli. This contrasts to global GlyRa1 deficient mice showing enhanced startle response. Consistently, CaKO mice also showed inhibited startle response. We next measured synaptic transmission and Gly-activated currents in spinal neurons without and with GlyRa1 deletion. To our surprise, depletion of GlyRa1 from GlyT2+ neurons selectively reduced the amplitude of Gly-activated current without significantly altering glycinergic IPSCs and glutamatergic EPSCs in GlKO-tdTomato mice. RNA sequencing data from both mutant mouse lines showed an increase in the expression level of the delta subunit of GABAA receptor in brainstem, consistent with the results of our capillary electrophoresis protein assay. These data demonstrate GlyRα1 subunits expressed in non-synaptic sites of GlyT2+ interneurons contribute to the regulation of motor function and startle response. These extrasynaptic GlyRa1 subunits may be a potential therapeutic target for GlyR-involved neurological diseases.

Scientific Focus Area: Neuroscience

This page was last updated on Tuesday, August 6, 2024

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