As an essential element for cellular function, divalent zinc is a cofactor in a large number enzymes and regulatory proteins. Since the surprising discovery that zinc is concentrated within synaptic vesicles in many excitatory synapses in the brain, including in more than 50% of excitatory presynaptic terminals in neocortical areas, numerous investigators have studied the possible roles of this metal during neurotransmission. Nonetheless, due to the paucity of zinc?selective tools optimized for neurobiological studies, the physiological roles of zinc during synaptic transmission remained elusive until recently. Our recent studies, funded by this grant, used novel tools for chelating and tracking zinc in central synapses and established zinc as an inhibitory neuromodulator in excitatory synapses. In response to a single presynaptic action potential, synaptic zinc is released and inhibits postsynaptic glutamate AMPA receptors (AMPARs). Moreover, during repetitive synaptic stimulation, zinc inhibits extrasynaptic glutamate NMDA receptors (NMDARs) and is necessary along with GPR39, a putative metabotropic zinc-sensing receptor, for activation of endocannabinoid signaling and glutamate release inhibition. These effects are experience-dependent because loud sound reduced presynaptic zinc levels and abolished zinc inhibition of AMPARs, implicating zinc in experience-dependent AMPAR synaptic plasticity. The establishment of a novel endogenous neuromodulator, acting in many excitatory synapses throughout the brain, reveals the significance of the work and poses three questions of fundamental importance to excitatory synaptic signaling and auditory processing: a) what are the dynamics of the different forms of zinc-mediated inhibition and how do they interact among themselves and with glutamate neurotransmission to shape excitatory glutamatergic signaling, b) what are the molecular mechanisms underlying long-lasting, activity-dependent changes in presynaptic zinc levels and how do they interact with other established plasticity mechanisms, and c) what are the characteristics of auditory stimuli that trigger zinc release in vivo and how does zinc release affect spontaneous and sound-evoked activity in awake animals. Answering these questions will contribute significantly not only to the fields of zinc biology and hearing research, but will also reveal general mechanisms that will be of great interest to the wider neuroscience community.
In Aims 1 and 2, we will employ in vitro brain slice experiments and use auditory brainstem synapses as models for studying the role of zinc in neurotransmission and plasticity.
In Aim 3, we will employ in vivo imaging to investigate the role of these mechanisms in auditory cortical processing in unanesthetized mice.
This research will test several novel hypotheses regarding the interactions between zinc, NMDA receptors (NMDARs) and AMPA receptors (AMPARs). These interactions are fundamental to our understanding of synaptic transmission and auditory processing. Because zinc, NMDAR and AMPARs are found in many brain areas and are associated with several disorders, such as epilepsy, hyperekplexia, schizophrenia, Alzheimer?s disease, tinnitus and pain processing, this research is relevant to those aspects of the NIH mission aimed at improving health through understanding pathophysiological mechanisms in disorders causing disability.
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