Na_V1.1 is essential for proprioceptive signaling and motor behaviors

Abstract

The mammalian voltage-gated sodium channel (NaV), NaV1.1, has been well-studied in the central nervous system; conversely, its contribution to peripheral sensory neuron function is more enigmatic. Here, we report a new role for peripherally expressed NaV1.1 in murine motor behaviors. RNAscope analysis found 100% of proprioceptors express NaV1.1 transcript, consistent with in vitro patch clamp recordings showing this channel is required for repetitive firing in proprioceptors. Notably, genetic deletion of NaV1.1 in all sensory neurons caused profound motor coordination deficits in homozygous conditional knockout animals of both sexes, a phenotype similar to conditional Piezo2-knockout animals. Movement deficits were also observed in heterozygotes, demonstrating that NaV1.1 haploinsufficiency in sensory neurons leads to motor deficiencies. This behavioral phenotype was not due to reduced proprioceptor numbers or abnormal muscle spindle formation; however, we observed decreased proprioceptor innervation of motor neurons in the spinal cord in conditional knockouts, indicating loss of NaV1.1 in sensory neurons alters spinal cord circuitry. Ex vivo muscle afferent recordings also support the notion that loss of NaV1.1 leads to aberrant proprioceptor function. Collectively, these data provide the first evidence that NaV1.1 in mammalian sensory neurons is essential for motor coordination. Importantly, human patients harboring NaV1.1 loss-of-function mutations often present with motor delays and ataxia. Thus, our data suggest sensory neuron dysfunction may contribute to the clinical manifestations and co-morbidities of neurological disorders in which NaV1.1 function is compromised.