Neurons in the avian nucleus magnocellularis and mammalian ventral cochlear nucleus passage the timing of phase-locked action potentials with great precision. Their ability to preserve timing is made possible by a variety of cellular adaptations at the membrane level, and is essential for the key role of these neurons in the localization of sound. While these neurons have long been known to be contacted by GABAergic axons, the function of such putatively inhibitory inputs is poorly understood. This is important to clarify in part because GABA receptors are a common pharmacological target and are implicated in a variety of neurological disorders. The goal of the proposed research is to determine how synaptically-released GABA can modify signals generated by auditory nerve fibers. This will be accomplished using a brain slice preparation of the chick nucleus magnocellularis in which individual cells will be patch clamped, and single excitatory and inhibitory presynaptic axons separately stimulated. We will determine the mechanisms of GABA release and postsynaptic GABA action by monitoring of postsynaptic GABAA receptor activation while measuring presynaptic calcium accumulation of GABAergic synapses, exploring a newly discovered phenomenon that GABA release from the synapses becomes desynchronized during stimulus trains. We will also use stimulation of excitatory and inhibitory fibers to determine how the synapses interact, either at the postsynaptic, electrical level, or at the presynaptic level through transmitter diffusion to presynaptic modulatory receptors of the GABAB subtype. The kinetics of activation of GABA receptors will be determined using rapid release of chemically-caged neurotransmitter in order to determine the relative time scales of pre- and postsynaptic actions of the GABA. This work will also examine the observation that presynaptic GABA receptors can have a potentiating effect of excitatory transmission in the cochlear nucleus, apparently at odds with the classical inhibitory role ascribed to GABA. The proposed research will clarify how GABA can facilitate the relay functions of these neurons and provide new clues as to how GABAergic drugs might modify sensory processing in humans.
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