| First Author | Wiessler AL | Year | 2024 |
| Journal | J Neurosci | Volume | 44 |
| Issue | 2 | PubMed ID | 37963764 |
| Mgi Jnum | J:346212 | Mgi Id | MGI:7614231 |
| Doi | 10.1523/JNEUROSCI.0837-23.2023 | Citation | Wiessler AL, et al. (2024) Role of the Glycine Receptor beta Subunit in Synaptic Localization and Pathogenicity in Severe Startle Disease. J Neurosci 44(2) |
| abstractText | 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 alpha1 and beta subunits that localizes at postsynaptic sites and replaces embryonically expressed GlyRalpha2 homomers. The human GlyR variants of GLRA1 and GLRB, dominant and recessive, have been intensively studied in vitro. However, the role of unaffected GlyRbeta, essential for synaptic GlyR localization, in the presence of mutated GlyRalpha1 in vivo is not fully understood. Here, we used knock-in mice expressing endogenous mEos4b-tagged GlyRbeta that were crossed with mouse Glra1 startle disease mutants. We explored the role of GlyRbeta under disease conditions in mice carrying a missense mutation (shaky) or resulting from the loss of GlyRalpha1 (oscillator). Interestingly, synaptic targeting of GlyRbeta was largely unaffected in both mouse mutants. While synaptic morphology appears unaltered in shaky animals, synapses were notably smaller in homozygous oscillator animals. Hence, GlyRbeta enables transport of functionally impaired GlyRalpha1 missense variants to synaptic sites in shaky animals, which has an impact on the efficacy of possible compensatory mechanisms. The observed enhanced GlyRalpha2 expression in oscillator animals points to a compensation by other GlyRalpha subunits. However, trafficking of GlyRalpha2beta complexes to synaptic sites remains functionally insufficient, and homozygous oscillator mice 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. |
