Project 2: Excitatory/Inhibitory Balance
P.I.: Francisco J. Alvarez, Ph.D.
Adjunct Professor, Department of Neuroscience, Cell Biology & Physiology
"Motoneurons control the activity in our muscles, but their function is in turn modulated by a fine balance between excitatory and inhibitory influences. We suspect that deficits in reacquiring this balance following nerve injury and regeneration are partly responsible for the incomplete restoration of motor function."
After peripheral nerve injuries, motor and sensory axons can regenerate and reestablish connectivity with muscle. However, despite recovery of muscle strength restored motor function is frequently abnormal. One possibility is that alterations in motor circuits at the level of the spinal cord prevent full functional recovery. In project 2 we will test the hypothesis that postsynaptic inhibitory inputs are reorganized over motoneurons axotomized after a nerve injury and this creates imbalances in inhibition that could generate abnormal motor output.
Our preliminary data show that inhibitory and excitatory synapses are differentially remodeled over axotomized motoneurons. Imbalances might occur if synaptic remodeling results in different proportions of excitatory and inhibitory inputs or because newly formed inhibitory synapses display altered properties or if inhibitory inputs from different sources are remodeled differently. It is unknown if possible imbalances are more or less permanent or how they differ between motoneurons that regenerate and reinnervate muscle with those that do not regenerate. We will investigate each of these possibilities in three specific aims. Aim 1 will test the hypothesis that imbalances in inhibitory/excitatory ratios are created because different properties of inhibitory and excitatory synapse remodeling on axotomized motoneurons. Aim 2 will test the hypothesis that inhibitory synapses with altered properties arise because failures in recapitulating mechanisms of inhibitory synapse maturation. Aim 3 will test the hypothesis that alterations might differentially affect inhibitory synapses from different interneurons and circuits.
We will use the same nerve injury model used in Projects 1 & 5, resection of the tibialis nerve supplying triceps surae muscles, with or without resuture to prevent or allow regeneration. We will use rats as animal model in aims 1 and 2. In aim 3 we will use transgenic mice that genetically encode EGFP inside the axons of different spinal inhibitory interneurons and permits isolation of specific circuits for analysis. At the completion of these aims we will have tested the possibility that inhibitory inputs become altered over axotomized motoneurons before, during and after peripheral nerve regeneration. This information will suggest whether or not remodeling of inhibitory inputs is significant and could contribute to permanent alterations in motor function. It is expected this workwill provide valuable information to understand mechanisms that hamper functional recovery after nerve injuries.