Grant: Project Grant

Movement is guided by sensory feedback, which is especially important after spinal cord injury (SCI) when the control of movement by the brain is impaired. We recently discovered that GABAA receptors located on sensory axons are crucial for enabling sensory transmission toward motoneurons, aiding associated reflexes. This made us wonder whether axonal GABAA receptors are crucial for the more fundamental function of perception of limb position (proprioception), by facilitating sensory axon transmission toward the brain. Our pilot studies show that genetic ablation of axonal GABAA receptors leads to a dramatic loss of proprioception and movement accuracy, suggesting that targeting axonal GABA might be a promising approach for augmenting residual sensorimotor function after SCI. Thus, we will in Aim 1 examine the hypothesis that GABAA receptors on sensory axons are crucial for sensory transmission toward the brain, including after SCI. The experiments will involve recording from proprioceptive axons in the spinal cord of mice with GABA receptors genetically ablated. Then in Aim 2 we will examine the hypothesis that specialized GABAergic neurons and astrocytes provide the GABA that regulates the sensory axons, with astrocytes becoming critical after SCI. The experiments will involve optogenetically activating or inhibiting the GABAergic neurons or astrocytes. In Aim 3 we will examine the core hypothesis that axonal GABA is important for perception of movement, and treatments that augment neuronal and astrocyte sources of this GABA improve conduction and sensorimotor function in mice and humans, including clinically applicable pharmacological and nerve stimulation treatments. The experiments will measure movement accuracy in a ladder walking task in mice with genetic ablations of GABAergic circuits, and sensory transmission in mice and humans. In summary, augmenting axonal GABA with clinically applicable treatments may help restore proprioception and movement after SCI.