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NaV1.1 is essential for proprioceptive signaling and motor behaviors

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Titel: NaV1.1 is essential for proprioceptive signaling and motor behaviors
Autoren: Cyrrus M Espino, Cheyanne M Lewis, Serena Ortiz, Miloni S Dalal, Snigdha Garlapalli, Kaylee M Wells, Darik A O'Neil, Katherine A Wilkinson, Theanne N Griffith
Quelle: eLife
eLife, Vol 11 (2022)
eLife, vol 11
Verlagsinformationen: Cold Spring Harbor Laboratory, 2022.
Publikationsjahr: 2022
Schlagwörter: Male, 0301 basic medicine, Mouse, proprioception, Medical Physiology, Action Potentials (mesh), Action Potentials, 3208 Medical Physiology (for-2020), Na(v)1, neuroscience, Mice, Proprioception (mesh), 31 Biological sciences (for-2020), voltage-gated sodium channel, 2.1 Biological and endogenous factors, Animals (mesh), Biology (General), 32 Biomedical and Clinical Sciences (for-2020), Male (mesh), Neurosciences (rcdc), Mice, Knockout, Humans (mesh), 0303 health sciences, motor function, Mice (mesh), Biological Sciences, 3209 Neurosciences (for-2020), Sensory Receptor Cells (mesh), Knockout (mesh), 3. Good health, Biological sciences, Chemistry, Neurological, Medicine, Female, somatosensation, Sensory Receptor Cells, QH301-705.5, Knockout, Science, Clinical Sciences, 0601 Biochemistry and Cell Biology (for), NAV1.1 Voltage-Gated Sodium Channel (mesh), 03 medical and health sciences, 42 Health sciences (for-2020), Genetics, Animals, Humans, 3202 Clinical Sciences (for-2020), mouse, Biomedical and Clinical Sciences, Genetics (rcdc), Neurological (hrcs-hc), Nav1.1, Neurosciences, Health sciences, 2.1 Biological and endogenous factors (hrcs-rac), electrophysiology, Proprioception, NAV1.1 Voltage-Gated Sodium Channel, 32 Biomedical and clinical sciences (for-2020), Female (mesh), Biochemistry and Cell Biology, Neuroscience
Beschreibung: The voltage-gated sodium channel (NaV), NaV1.1, is well-studied in the central nervous system; conversely, its contribution to peripheral sensory neuron function is more enigmatic. Here, we identify a new role for NaV1.1 in mammalian proprioception. RNAscope analysis and in vitro patch clamp recordings in genetically identified mouse proprioceptors show ubiquitously channel expression and significant contributions to intrinsic excitability. Notably, genetic deletion of NaV1.1 in sensory neurons caused profound and visible motor coordination deficits in conditional knockout mice of both sexes, similar to conditional Piezo2-knockout animals, suggesting this channel is a major contributor to sensory proprioceptive transmission. Ex vivo muscle afferent recordings conditional knockout mice found that loss of NaV1.1 leads to inconsistent and unreliable proprioceptor firing characterized by action potential failures during static muscle stretch; conversely, afferent responses to dynamic vibrations were unaffected. This suggests that while a combination of Piezo2 and other NaV isoforms are sufficient to elicit activity in response to transient stimuli, NaV1.1 is required for transmission of receptor potentials generated during sustained muscle stretch. Impressively, recordings from afferents of heterozygous conditional knockout animals were similarly impaired, and heterozygous conditional knockout mice also exhibited motor behavioral deficits. Thus, NaV1.1 haploinsufficiency in sensory neurons impairs both proprioceptor function and motor behaviors. Importantly, human patients harboring NaV1.1 loss-of-function mutations often present with motor delays and ataxia; therefore, our data suggest sensory neuron dysfunction contributes to the clinical manifestations of neurological disorders in which NaV1.1 function is compromised. Collectively, we present the first evidence that NaV1.1 is essential for mammalian proprioceptive signaling and behaviors.
Publikationsart: Article
Other literature type
Dateibeschreibung: application/pdf
ISSN: 2050-084X
DOI: 10.1101/2022.05.05.490851
DOI: 10.7554/elife.79917
Zugangs-URL: https://pubmed.ncbi.nlm.nih.gov/36278870
https://doaj.org/article/6bacc82af845487687938babfabebd88
https://escholarship.org/content/qt5r96s5gc/qt5r96s5gc.pdf
https://escholarship.org/uc/item/5r96s5gc
Rights: CC BY
Dokumentencode: edsair.doi.dedup.....6ad6b6f4ed0a9be6cde6e75a749c0b2d
Datenbank: OpenAIRE
Beschreibung
Abstract:The voltage-gated sodium channel (NaV), NaV1.1, is well-studied in the central nervous system; conversely, its contribution to peripheral sensory neuron function is more enigmatic. Here, we identify a new role for NaV1.1 in mammalian proprioception. RNAscope analysis and in vitro patch clamp recordings in genetically identified mouse proprioceptors show ubiquitously channel expression and significant contributions to intrinsic excitability. Notably, genetic deletion of NaV1.1 in sensory neurons caused profound and visible motor coordination deficits in conditional knockout mice of both sexes, similar to conditional Piezo2-knockout animals, suggesting this channel is a major contributor to sensory proprioceptive transmission. Ex vivo muscle afferent recordings conditional knockout mice found that loss of NaV1.1 leads to inconsistent and unreliable proprioceptor firing characterized by action potential failures during static muscle stretch; conversely, afferent responses to dynamic vibrations were unaffected. This suggests that while a combination of Piezo2 and other NaV isoforms are sufficient to elicit activity in response to transient stimuli, NaV1.1 is required for transmission of receptor potentials generated during sustained muscle stretch. Impressively, recordings from afferents of heterozygous conditional knockout animals were similarly impaired, and heterozygous conditional knockout mice also exhibited motor behavioral deficits. Thus, NaV1.1 haploinsufficiency in sensory neurons impairs both proprioceptor function and motor behaviors. Importantly, human patients harboring NaV1.1 loss-of-function mutations often present with motor delays and ataxia; therefore, our data suggest sensory neuron dysfunction contributes to the clinical manifestations of neurological disorders in which NaV1.1 function is compromised. Collectively, we present the first evidence that NaV1.1 is essential for mammalian proprioceptive signaling and behaviors.
ISSN:2050084X
DOI:10.1101/2022.05.05.490851