Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants

Schaefer, Natascha; Signoret-Genest, Jérémy; Collenberg, Cora R. von; Wachter, Britta; Deckert, Jürgen; Tovote, Philip; Blum, Robert; Villmann, Carmen

doi:10.3389/fnmol.2020.00152

Cited by 9 publications

(7 citation statements)

References 55 publications

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“…GlyRs play important roles in the pathophysiology of startle diseases: mutations in the GlyR α1 and β subtypes are involved in the exaggerated startle response in humans and mice [ 43 – 45 ]. Homozygous spasmodic mice harboring a mutation in Glra1 displayed abnormally enhanced startle responses in response to acoustic stimuli [ 46 ]. By comparing the exaggerated startle response of Glra1 mutant mice to the decreased and delayed response of Glra4 mutant mice, we expect that mutations in the GlyR α4 and GlyR α1 genes induce distinct startle phenotypes in mice.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive behavioral analyses of mice with a glycine receptor alpha 4 deficiency

et al. 2023

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Glycine receptors (GlyRs) are ligand-gated chloride channels comprising alpha (α1–4) and β subunits. The GlyR subunits play major roles in the mammalian central nervous system, ranging from regulating simple sensory information to modulating higher-order brain function. Unlike the other GlyR subunits, GlyR α4 receives relatively little attention because the human ortholog lacks a transmembrane domain and is thus considered a pseudogene. A recent genetic study reported that the GLRA4 pseudogene locus on the X chromosome is potentially involved in cognitive impairment, motor delay and craniofacial anomalies in humans. The physiologic roles of GlyR α4 in mammal behavior and its involvement in disease, however, are not known. Here we examined the temporal and spatial expression profile of GlyR α4 in the mouse brain and subjected Glra4 mutant mice to a comprehensive behavioral analysis to elucidate the role of GlyR α4 in behavior. The GlyR α4 subunit was mainly enriched in the hindbrain and midbrain, and had relatively lower expression in the thalamus, cerebellum, hypothalamus, and olfactory bulb. In addition, expression of the GlyR α4 subunit gradually increased during brain development. Glra4 mutant mice exhibited a decreased amplitude and delayed onset of the startle response compared with wild-type littermates, and increased social interaction in the home cage during the dark period. Glra4 mutants also had a low percentage of entries into open arms in the elevated plus-maze test. Although mice with GlyR α4 deficiency did not show motor and learning abnormalities reported to be associated in human genomics studies, they exhibited behavioral changes in startle response and social and anxiety-like behavior. Our data clarify the spatiotemporal expression pattern of the GlyR α4 subunit and suggest that glycinergic signaling modulates social, startle, and anxiety-like behaviors in mice.

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Section: Discussionmentioning

confidence: 99%

Comprehensive behavioral analyses of mice with a glycine receptor alpha 4 deficiency

et al. 2023

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“…[40] Disturbances in spinal cord signal processing is associated with different neurological diseases such as stiff baby syndrome, stiff person syndrome, epilepsy, autism, and panic disorders. [18][19][20][21][22] The underlying molecular and cellular pathologies are not completely understood yet, forcing us to develop a 3D model system that allows studying disease mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Disturbances in inhibitory signal transduction processes are associated with different forms of neurological disorders, such as hyperekplexia (OMIM 14 900, startle disease, stiff baby syndrome), stiff person syndrome, epilepsy, pain sensitization, autism, and agoraphobia. [18][19][20][21][22] The underlying molecular and cellular mechanisms in those diseases are not fully understood yet, making a 3D cell culture system a suitable tool to provide better understanding of the disease pathologies.…”

Section: Introductionmentioning

confidence: 99%

Spinal Cord Neuronal Network Formation in a 3D Printed Reinforced Matrix—A Model System to Study Disease Mechanisms

Fischhaber

Faber

Bakırcı

et al. 2021

Adv Healthcare Materials

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3D cell cultures allow a better mimicry of the biological and mechanical environment of cells in vivo compared to 2D cultures. However, 3D cell cultures have been challenging for ultrasoft tissues such as the brain. The present study uses a microfiber reinforcement approach combining mouse primary spinal cord neurons in Matrigel with melt electrowritten (MEW) frames. Within these 3D constructs, neuronal network development is followed for 21 days in vitro. To evaluate neuronal development in 3D constructs, the maturation of inhibitory glycinergic synapses is analyzed using protein expression, the complex mechanical properties by assessing nonlinearity, conditioning, and stress relaxation, and calcium imaging as readouts. Following adaptation to the 3D matrix-frame, mature inhibitory synapse formation is faster than in 2D demonstrated by a steep increase in glycine receptor expression between days 3 and 10. The 3D expression pattern of marker proteins at the inhibitory synapse and the mechanical properties resemble the situation in native spinal cord tissue. Moreover, 3D spinal cord neuronal networks exhibit intensive neuronal activity after 14 days in culture. The spinal cord cell culture model using ultrasoft matrix reinforced by MEW fibers provides a promising tool to study and understand biomechanical mechanisms in health and disease.

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“…However, other behavioral tests (e.g., elevated plus maze, dark/light) lacked significant differences between mice with reduced GlyRβ levels and wild type controls. Therefore, a modulatory function for the GlyRβ subunit within glycinergic circuits in neuronal networks is important for fear and fear-related behaviors (Schaefer and others 2020).…”

Section: Altered Glycinergic Neurotransmission In Additional Disease ...mentioning

confidence: 99%

Startle Disease: New Molecular Insights into an Old Neurological Disorder

2022

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Startle disease (SD) is characterized by enhanced startle responses, generalized muscle stiffness, unexpected falling, and fatal apnea episodes due to disturbed feedback inhibition in the spinal cord and brainstem of affected individuals. Mutations within the glycine receptor (GlyR) subunit and glycine transporter 2 (GlyT2) genes have been identified in individuals with SD. Impaired inhibitory neurotransmission in SD is due to pre- and/or postsynaptic GlyR or presynaptic GlyT2 dysfunctions. Previous research has focused on mutated GlyRs and GlyT2 that impair ion channel/transporter function or trafficking. With insights provided by recently solved cryo–electron microscopy and X-ray structures of GlyRs, a detailed picture of structural transitions important for receptor gating has emerged, allowing a deeper understanding of SD at the molecular level. Moreover, studies on novel SD mutations have demonstrated a higher complexity of SD, with identification of additional clinical signs and symptoms and interaction partners representing key players for fine-tuning synaptic processes. Although our knowledge has steadily improved during the last years, changes in synaptic localization and GlyR or GlyT2 homeostasis under disease conditions are not yet completely understood. Combined proteomics, interactomics, and high-resolution microscopy techniques are required to reveal alterations in receptor dynamics at the synaptic level under disease conditions.

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Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants

Cited by 9 publications

References 55 publications

Comprehensive behavioral analyses of mice with a glycine receptor alpha 4 deficiency

Comprehensive behavioral analyses of mice with a glycine receptor alpha 4 deficiency

Spinal Cord Neuronal Network Formation in a 3D Printed Reinforced Matrix—A Model System to Study Disease Mechanisms

Startle Disease: New Molecular Insights into an Old Neurological Disorder

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