Schaefer, N;
Zheng, F;
van Brederode, J;
Berger, A;
Leacock, S;
Hirata, H;
Paige, CJ;
... Villmann, C; + view all
(2018)
Functional Consequences of the Postnatal Switch From Neonatal to Mutant Adult Glycine Receptor a 1 Subunits in the Shaky Mouse Model of Startle Disease.
Frontiers in Molecular Neuroscience
, 11
, Article 167. 10.3389/fnmol.2018.00167.
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Functional Consequences of the Postnatal Switch From Neonatal to Mutant Adult Glycine Receptor α1 Subunits in the Shaky Mouse Model of Startle Disease.pdf - Published Version Download (2MB) | Preview |
Abstract
Mutations in GlyR α1 or β subunit genes in humans and rodents lead to severe startle disease characterized by rigidity, massive stiffness and excessive startle responses upon unexpected tactile or acoustic stimuli. The recently characterized startle disease mouse mutant shaky carries a missense mutation (Q177K) in the β8-β9 loop within the large extracellular N-terminal domain of the GlyR α1 subunit. This results in a disrupted hydrogen bond network around K177 and faster GlyR decay times. Symptoms in mice start at postnatal day 14 and increase until premature death of homozygous shaky mice around 4–6 weeks after birth. Here we investigate the in vivo functional effects of the Q177K mutation using behavioral analysis coupled to protein biochemistry and functional assays. Western blot analysis revealed GlyR α1 subunit expression in wild-type and shaky animals around postnatal day 7, a week before symptoms in mutant mice become obvious. Before 2 weeks of age, homozygous shaky mice appeared healthy and showed no changes in body weight. However, analysis of gait and hind-limb clasping revealed that motor coordination was already impaired. Motor coordination and the activity pattern at P28 improved significantly upon diazepam treatment, a pharmacotherapy used in human startle disease. To investigate whether functional deficits in glycinergic neurotransmission are present prior to phenotypic onset, we performed whole-cell recordings from hypoglossal motoneurons (HMs) in brain stem slices from wild-type and shaky mice at different postnatal stages. Shaky homozygotes showed a decline in mIPSC amplitude and frequency at P9-P13, progressing to significant reductions in mIPSC amplitude and decay time at P18-24 compared to wild-type littermates. Extrasynaptic GlyRs recorded by bath-application of glycine also revealed reduced current amplitudes in shaky mice compared to wild-type neurons, suggesting that presynaptic GlyR function is also impaired. Thus, a distinct, but behaviorally ineffective impairment of glycinergic synapses precedes the symptoms onset in shaky mice. These findings extend our current knowledge on startle disease in the shaky mouse model in that they demonstrate how the progression of GlyR dysfunction causes, with a delay of about 1 week, the appearance of disease symptoms.
Type: | Article |
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Title: | Functional Consequences of the Postnatal Switch From Neonatal to Mutant Adult Glycine Receptor a 1 Subunits in the Shaky Mouse Model of Startle Disease |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.3389/fnmol.2018.00167 |
Publisher version: | http://doi.org/10.3389/fnmol.2018.00167 |
Language: | English |
Additional information: | Copyright © 2018 Schaefer, Zheng, van Brederode, Berger, Leacock, Hirata, Paige, Harvey, Alzheimer and Villmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
Keywords: | glycine receptor, startle disease, β8-β9 loop, mouse model, fast decay, shaky |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
URI: | https://discovery.ucl.ac.uk/id/eprint/10051619 |
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