<i>De Novo</i> Exon Duplication in a New Allele of Mouse <i>Glra1</i> (Spasmodic)

Holland, Katherine D.; Fleming, Michelle T.; Cheek, Susannah; Moran, Jennifer L.; Beier, David R.; Meisler, Miriam H.

doi:10.1534/genetics.106.065532

Cited by 12 publications

(11 citation statements)

References 13 publications

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“…In addition, a longer time window for righting has been shown for shaky mice (Schaefer et al, 2017 ). All together, these symptoms are similar to symptoms reported in cincinnati, oscillator, nmf11, spasmodic and spastic mice (Buckwalter et al, 1994 ; Holland et al, 2006 ; Traka et al, 2006 ; Becker et al, 2012 ; Schaefer et al, 2017 ). Patients are symptomatically treated by diazepam, a positive allosteric modulator of GABA A receptors (Praveen et al, 2001 ).…”

Section: Discussionsupporting

confidence: 81%

“…Spasmodic mice harbor the missense mutation A52S in the GlyR α1 subunit A loop, leading to decreased ligand affinity and potency (Ryan et al, 1994 ). Homozygous cincinnati and oscillator mice represent GlyR α1 subunit null mutations, the former caused by duplication of Glra1 exon 5, the latter due to a microdeletion in exon 8, both resulting in mRNA mis-splicing and truncated non-functional GlyR α1 subunits (Buckwalter et al, 1994 ; Holland et al, 2006 ). Spastic mice result from aberrant splicing of the GlyR β subunit mRNA, due to a LINE-1 element insertion in intron 6 (Becker et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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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

Schaefer

Zheng

Brederode

et al. 2018

Front. Mol. Neurosci.

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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.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Functional Consequences of the Postnatal Switch From Neonatal to Mutant Adult Glycine Receptor α1 Subunits in the Shaky Mouse Model of Startle Disease

Schaefer

Zheng

Brederode

et al. 2018

Front. Mol. Neurosci.

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“…There are two mouse models harboring mutations within the a1 subunit of the GlyR: cincinnati mice and oscillator (spd ot ), both unfortunately showing lethal phenotypes (Buckwalter et al 1994;Kling et al 1997;Holland et al 2006;Villmann et al 2009). Homozygous spd ot mice are lethal because of a premature stop codon in Glra1 (Buckwalter et al 1994).…”

Section: Mutations In Glycinergic Signalingmentioning

confidence: 99%

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Lepeta

Lourenco

Schweitzer

et al. 2016

Journal of Neurochemistry

281

220

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Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in diseaseassociated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders.

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“…As for human hyperekplexia (Holland et al, 2006) Cow, Myoclonus α1, nonsense mutation (Y24X) leading to a premature stop codon Naturally occurring, autosomal recessive…”

Section: Reduced Receptor Expressionmentioning

confidence: 99%

Native glycine receptor subtypes and their physiological roles

Lynch¹

2009

Neuropharmacology

341

333

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The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. They are also found presynaptically, where they modulate neurotransmitter release. Functional GlyRs are formed from a total of five subunits (alpha1-alpha4, beta). Although alpha subunits efficiently form homomeric GlyRs in recombinant expression systems, homomeric alpha1, alpha3 and alpha4 GlyRs are weakly expressed in adult neurons. In contrast, alpha2 homomeric GlyRs are abundantly expressed in embryonic neurons, although their numbers decline sharply by adulthood. Numerous lines of biochemical, biophysical, pharmacological and genetic evidence suggest the majority of glycinergic neurotransmission in adults is mediated by heteromeric alpha1beta GlyRs. Immunocytochemical co-localisation experiments suggest the presence of alpha2beta, alpha3beta and alpha4beta GlyRs at synapses in the adult mouse retina. Immunocytochemical and electrophysiological evidence also implicates alpha3beta GlyRs as important mediators of glycinergic inhibitory neurotransmission in nociceptive sensory neuronal circuits in peripheral laminae of the spinal cord dorsal horn. It is yet to be determined why multiple GlyR synaptic subtypes are differentially distributed in these and possibly other locations. The development of pharmacological agents that can discriminate strongly between different beta subunit-containing GlyR isoforms will help to address this issue, and thereby provide important insights into a variety of central nervous system functions including retinal signal processing and spinal pain mechanisms. Finally, agents that selectively potentiate different GlyR isoforms may be useful as therapeutic lead compounds for peripheral inflammatory pain and movement disorders such as spasticity.

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De Novo Exon Duplication in a New Allele of Mouse Glra1 (Spasmodic)

Cited by 12 publications

References 13 publications

Functional Consequences of the Postnatal Switch From Neonatal to Mutant Adult Glycine Receptor α1 Subunits in the Shaky Mouse Model of Startle Disease

Functional Consequences of the Postnatal Switch From Neonatal to Mutant Adult Glycine Receptor α1 Subunits in the Shaky Mouse Model of Startle Disease

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Native glycine receptor subtypes and their physiological roles

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