Vesicular zinc modulates neuronal excitability through its effects on synaptic and intrinsic properties. In the dorsal cochlear nucleus (DCN), an auditory brainstem nucleus, zinc containing terminals have been identified. However, the neuromodulatory role of synaptic zinc in the DCN or in any other auditory circuit remains unknown. The long term goal of this proposal is to unravel the neuromodulatory role of the synaptic zinc in the DCN. The central hypothesis is that synaptic zinc controls the excitability of the DCN circuit through activity- dependent modulation of the intrinsic and synaptic properties of the principal cells. In Aim 1, the role of synaptically released zinc on intrinsic properties and firing patterns of DCN principal neurons will be determined. For this purpose the membrane ionic conductance's modulated by synaptic Zn2+ will be identified using electrophysiological approaches. In Aim 2, the role of synaptically released zinc on synaptic properties of DCN principal neurons will be determined. To accomplish this, the cellular mechanism involved in the Zn2+-mediated modulation of endocannabinoid signaling in DCN principal neurons will be identified. We will employ electrophysiological, immunohistochemicals, and Ca2+ imaging techniques. These studies will provide a framework to understand the role of zinc in auditory processing.