Role of the Glycine Receptor β Subunit in Synaptic Localization and Pathogenicity in Severe Startle Disease

Author:

Wiessler Anna-Lena,Hasenmüller Ann-Sofie,Fuhl Isabell,Mille Clémence,Cortes Campo Orlando,Reinhard Nicola,Schenk Joachim,Heinze Katrin G.,Schaefer NataschaORCID,Specht Christian G.,Villmann CarmenORCID

Abstract

Startle disease is due to the disruption of recurrent inhibition in the spinal cord. Most common causes are genetic variants in genes (GLRA1,GLRB) encoding inhibitory glycine receptor (GlyR) subunits. The adult GlyR is a heteropentameric complex composed of α1 and β subunits that localizes at postsynaptic sites and replaces embryonically expressed GlyRα2 homomers. The human GlyR variants ofGLRA1andGLRB, dominant and recessive, have been intensively studied in vitro. However, the role of unaffected GlyRβ, essential for synaptic GlyR localization, in the presence of mutated GlyRα1 in vivo is not fully understood. Here, we used knock-in mice expressing endogenous mEos4b-tagged GlyRβ that were crossed with mouseGlra1startle disease mutants. We explored the role of GlyRβ under disease conditions in mice carrying a missense mutation (shaky) or resulting from the loss of GlyRα1 (oscillator). Interestingly, synaptic targeting of GlyRβ was largely unaffected in both mouse mutants. While synaptic morphology appears unaltered inshakyanimals, synapses were notably smaller in homozygousoscillatoranimals. Hence, GlyRβ enables transport of functionally impaired GlyRα1 missense variants to synaptic sites inshakyanimals, which has an impact on the efficacy of possible compensatory mechanisms. The observed enhanced GlyRα2 expression inoscillatoranimals points to a compensation by other GlyRα subunits. However, trafficking of GlyRα2β complexes to synaptic sites remains functionally insufficient, and homozygousoscillatormice still die at 3 weeks after birth. Thus, both functional and structural deficits can affect glycinergic neurotransmission in severe startle disease, eliciting different compensatory mechanisms in vivo.

Funder

Deutsche Forschungsgemeinschaft

JMU | Graduate School of Life Sciences, Julius-Maximilians-Universität Würzburg

Universidad Del Norte, Direccion de Gestion y Desarrollo Académico

Scientia program of the JMU Wuerzburg

Willy Robert Pitzer Stiftung

Agence Nationale de la Recherche

Publisher

Society for Neuroscience

Subject

General Neuroscience

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