Functional Consequences of the Postnatal Switch From Neonatal to Mutant Adult Glycine Receptor α1 Subunits in the Shaky Mouse Model of Startle Disease Article Swipe
Natascha Schaefer
,
Fang Zheng
,
Johannes van Brederode
,
Alexandra Berger
,
Sophie Leacock
,
Hiromi Hirata
,
Christopher J. Paige
,
Victoria L. Harvey
,
Christian Alzheimer
,
Carmen Villmann
·
YOU?
·
· 2018
· Open Access
·
· DOI: https://doi.org/10.3389/fnmol.2018.00167
YOU?
·
· 2018
· Open Access
·
· DOI: https://doi.org/10.3389/fnmol.2018.00167
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.
Related Topics
Concepts
Glycine receptor
Startle response
Biology
Startle reaction
Neuroscience
Mutant
Missense mutation
Internal medicine
Endocrinology
Mutation
Glycine
Medicine
Genetics
Reflex
Gene
Amino acid
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.3389/fnmol.2018.00167
- OA Status
- gold
- Cited By
- 13
- References
- 54
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2801302314
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W2801302314Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.3389/fnmol.2018.00167Digital Object Identifier
- Title
-
Functional Consequences of the Postnatal Switch From Neonatal to Mutant Adult Glycine Receptor α1 Subunits in the Shaky Mouse Model of Startle DiseaseWork title
- Type
-
articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2018Year of publication
- Publication date
-
2018-05-24Full publication date if available
- Authors
-
Natascha Schaefer, Fang Zheng, Johannes van Brederode, Alexandra Berger, Sophie Leacock, Hiromi Hirata, Christopher J. Paige, Victoria L. Harvey, Christian Alzheimer, Carmen VillmannList of authors in order
- Landing page
-
https://doi.org/10.3389/fnmol.2018.00167Publisher landing page
- Open access
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
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https://doi.org/10.3389/fnmol.2018.00167Direct OA link when available
- Concepts
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Glycine receptor, Startle response, Biology, Startle reaction, Neuroscience, Mutant, Missense mutation, Internal medicine, Endocrinology, Mutation, Glycine, Medicine, Genetics, Reflex, Gene, Amino acidTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
13Total citation count in OpenAlex
- Citations by year (recent)
-
2024: 4, 2023: 2, 2022: 2, 2021: 2, 2020: 1Per-year citation counts (last 5 years)
- References (count)
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54Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.mutant | 38, 141 |
| abstract_inverted_index.onset, | 209 |
| abstract_inverted_index.severe | 14 |
| abstract_inverted_index.showed | 156, 233 |
| abstract_inverted_index.slices | 221 |
| abstract_inverted_index.times. | 74 |
| abstract_inverted_index.within | 49 |
| abstract_inverted_index.(Q177K) | 44 |
| abstract_inverted_index.P9-P13, | 242 |
| abstract_inverted_index.Western | 119 |
| abstract_inverted_index.already | 174 |
| abstract_inverted_index.animals | 131 |
| abstract_inverted_index.assays. | 118 |
| abstract_inverted_index.carries | 40 |
| abstract_inverted_index.causes, | 327 |
| abstract_inverted_index.changes | 158 |
| abstract_inverted_index.coupled | 112 |
| abstract_inverted_index.current | 269, 307 |
| abstract_inverted_index.decline | 235 |
| abstract_inverted_index.disease | 16, 36, 311, 338 |
| abstract_inverted_index.effects | 104 |
| abstract_inverted_index.glycine | 265 |
| abstract_inverted_index.healthy | 154 |
| abstract_inverted_index.massive | 20 |
| abstract_inverted_index.network | 67 |
| abstract_inverted_index.pattern | 181 |
| abstract_inverted_index.present | 205 |
| abstract_inverted_index.protein | 114 |
| abstract_inverted_index.reduced | 268 |
| abstract_inverted_index.results | 61 |
| abstract_inverted_index.rodents | 11 |
| abstract_inverted_index.stages. | 230 |
| abstract_inverted_index.startle | 15, 24, 35, 194, 310 |
| abstract_inverted_index.subunit | 6, 125 |
| abstract_inverted_index.tactile | 28 |
| abstract_inverted_index.weight. | 161 |
| abstract_inverted_index.whether | 198 |
| abstract_inverted_index.β8-β9 | 47 |
| abstract_inverted_index.However, | 162 |
| abstract_inverted_index.Symptoms | 75 |
| abstract_inverted_index.acoustic | 30 |
| abstract_inverted_index.activity | 180 |
| abstract_inverted_index.analysis | 111, 121, 163 |
| abstract_inverted_index.appeared | 153 |
| abstract_inverted_index.clasping | 168 |
| abstract_inverted_index.compared | 255, 274 |
| abstract_inverted_index.deficits | 200 |
| abstract_inverted_index.diazepam | 187 |
| abstract_inverted_index.disease. | 195 |
| abstract_inverted_index.findings | 304 |
| abstract_inverted_index.function | 282 |
| abstract_inverted_index.hydrogen | 65 |
| abstract_inverted_index.improved | 184 |
| abstract_inverted_index.increase | 84 |
| abstract_inverted_index.missense | 42 |
| abstract_inverted_index.mutation | 43, 108 |
| abstract_inverted_index.neurons, | 277 |
| abstract_inverted_index.obvious. | 144 |
| abstract_inverted_index.precedes | 296 |
| abstract_inverted_index.recently | 33 |
| abstract_inverted_index.recorded | 261 |
| abstract_inverted_index.revealed | 122, 169, 267 |
| abstract_inverted_index.stimuli. | 31 |
| abstract_inverted_index.subunit. | 59 |
| abstract_inverted_index.symptoms | 139, 298 |
| abstract_inverted_index.synapses | 295 |
| abstract_inverted_index.vivo</i> | 102 |
| abstract_inverted_index.Mutations | 0 |
| abstract_inverted_index.amplitude | 238, 249 |
| abstract_inverted_index.different | 228 |
| abstract_inverted_index.disrupted | 64 |
| abstract_inverted_index.distinct, | 288 |
| abstract_inverted_index.excessive | 23 |
| abstract_inverted_index.frequency | 240 |
| abstract_inverted_index.hind-limb | 167 |
| abstract_inverted_index.impaired. | 175, 285 |
| abstract_inverted_index.knowledge | 308 |
| abstract_inverted_index.performed | 211 |
| abstract_inverted_index.postnatal | 80, 133, 229 |
| abstract_inverted_index.premature | 86 |
| abstract_inverted_index.responses | 25 |
| abstract_inverted_index.rigidity, | 19 |
| abstract_inverted_index.stiffness | 21 |
| abstract_inverted_index.symptoms. | 339 |
| abstract_inverted_index.wild-type | 128, 223, 257, 276 |
| abstract_inverted_index.N-terminal | 53 |
| abstract_inverted_index.amplitudes | 270 |
| abstract_inverted_index.appearance | 336 |
| abstract_inverted_index.behavioral | 110 |
| abstract_inverted_index.expression | 126 |
| abstract_inverted_index.functional | 103, 117, 199 |
| abstract_inverted_index.homozygous | 89, 150 |
| abstract_inverted_index.impairment | 292 |
| abstract_inverted_index.phenotypic | 208 |
| abstract_inverted_index.recordings | 213 |
| abstract_inverted_index.reductions | 246 |
| abstract_inverted_index.suggesting | 278 |
| abstract_inverted_index.treatment, | 188 |
| abstract_inverted_index.unexpected | 27 |
| abstract_inverted_index.whole-cell | 212 |
| abstract_inverted_index.demonstrate | 320 |
| abstract_inverted_index.dysfunction | 326 |
| abstract_inverted_index.glycinergic | 202, 294 |
| abstract_inverted_index.homozygotes | 232 |
| abstract_inverted_index.hypoglossal | 215 |
| abstract_inverted_index.ineffective | 291 |
| abstract_inverted_index.investigate | 99, 197 |
| abstract_inverted_index.motoneurons | 216 |
| abstract_inverted_index.presynaptic | 280 |
| abstract_inverted_index.progressing | 243 |
| abstract_inverted_index.progression | 323 |
| abstract_inverted_index.significant | 245 |
| abstract_inverted_index.<i>Shaky</i> | 231 |
| abstract_inverted_index.<i>shaky</i> | 39, 90, 130, 151, 225, 272, 301, 314 |
| abstract_inverted_index.behaviorally | 290 |
| abstract_inverted_index.biochemistry | 115 |
| abstract_inverted_index.coordination | 172, 177 |
| abstract_inverted_index.littermates. | 258 |
| abstract_inverted_index.Extrasynaptic | 259 |
| abstract_inverted_index.characterized | 17, 34 |
| abstract_inverted_index.extracellular | 52 |
| abstract_inverted_index.significantly | 185 |
| abstract_inverted_index.pharmacotherapy | 190 |
| abstract_inverted_index.bath-application | 263 |
| abstract_inverted_index.neurotransmission | 203 |
| cited_by_percentile_year.max | 98 |
| cited_by_percentile_year.min | 89 |
| corresponding_author_ids | https://openalex.org/A5036540118 |
| countries_distinct_count | 5 |
| institutions_distinct_count | 10 |
| corresponding_institution_ids | https://openalex.org/I25974101 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.7599999904632568 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.59213684 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |