AMPA receptor inhibition by synaptically released zinc

Significance Ionotropic glutamate AMPA receptors (AMPARs) play a fundamental role in normal function and plasticity of the brain, and they are also involved in many brain disorders. Despite the central role of AMPARs in neurobiology, the modulation of synaptic AMPA responses by endogenous modulators remains not well understood. Here, in three synapses found in two different brain areas, we provide the first evidence, to our knowledge, that endogenous zinc is coreleased with glutamate and modulates the strength of synaptic AMPAR responses. Because in many neocortical areas more than 50% of excitatory presynaptic terminals contain zinc within their glutamatergic vesicles, our findings establish zinc as a general neuromodulator that allows for fine-tuning and plasticity of glutamatergic fast synaptic transmission in the brain. The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.

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