Neuroengineering & Medicine Seminar: Differential Encoding of Mammalian Proprioception by Voltage Gated Sodium Channels

Abstract: Proprioception is our sense of internal spatial orientation and is required for motor reflexes and purposeful movement. How proprioceptive signals are transmitted by peripheral proprioceptors remains poorly understood. Our work on voltage gated sodium channels (Navs) shows that the Nav1.1 and Nav1.6 subtypes play unique and non-redundant roles in mammalian proprioception. Deletion of either Nav1.1 or Nav1.6 in peripheral sensory neurons (Nav1.1cko and Nav1.6cko) results in distinct behavioral phenotypes and has differential consequences on muscle-spindle proprioceptor electrical activity. We also observe differing contributions of Nav1.1 and Nav1.6 to proprioceptor-motor neuron monosynaptic reflex circuitry in the spinal cord. Loss of Nav1.6, but not Nav1.1, severely impaired the monosynaptic reflex response in mice capable of weight-bearing locomotion. These changes in sensory-motor circuitry in the spinal cord were accompanied by changes in intrinsic muscle properties in Nav1.6cko mice, but not Nav1.1cko mice. At the cellular level, immunolabeling experiments in muscle spindles show Nav1.1 and Nav1.6 localize to different proprioceptor compartments and support the notion that Nav1.6 plays a specific role in initiating proprioceptor transmission, whereas Nav1.1 is essential for maintaining proprioceptor excitability. We have recently developed an intersectional CRISPR/Cas9 approach to delete Nav1.1 and Nav1.6 selectively in proprioceptors, which is not currently feasible with traditional genetic approaches. Ongoing experiments are determining how acute loss of either channel in adulthood affects proprioceptor function and motor behaviors.