Grant: Project Grant

This proposal explores a fundamentally new mechanism for regulating nerve conduction in the spinal cord, with far reaching implications to understanding normal sensorimotor control and opening new therapeutic opportunities for restoring locomotion after spinal cord injury (SCI). While the primary inhibitory transmitter in the spinal cord is GABA, we have discovered that GABA seems to have a paradoxical excitatory action on conduction in sensory axons, which likely generalizes to other types of axons. That is, our recent finding that extrasynaptic GABA receptors are adjacent to the sodium channels in sensory axons has led us to the idea that sodium spike transmission in sensory axons is facilitated by these GABA receptors, by virtue of their long-lasting depolarizing excitatory actions (termed PAD). To test this idea we will record from inside fine branches of sensory axons in the spinal cord of mice while activating the neuronal circuits that provide GABA to the axons, using genetically modified mice that allow light activation and visualization of specific GABA neurons, and also traditional nerve stimulation protocols known to evoke PAD. We will also make recordings from motoneurons in mice and single motor units in humans to further confirm that activating these GABA neurons (and PAD, indirectly with nerve stimulation in humans) increases sensory transmission to motoneurons, and also to demonstrate the relevance of the animal studies to humans. Finally, we will repeat these studies in mice and humans with SCI, and explore whether excess extrasynaptic GABA contributes to motor disorders. Our preliminary results suggest that drugs that selectively block extrasynaptic GABA receptors inhibit spasms and markedly improve walking after SCI. These drugs lack the negative sedative side effects of other drugs used in SCI, and are already being tested by other laboratories in human stroke patients, and thus now hold considerable promise for treating SCI.