Bidirectional Long-Term Synaptic Zinc Plasticity at Mouse Glutamatergic Synapses

Abstract

AbstractSynaptic zinc is coreleased with glutamate to modulate neurotransmission in many excitatory synapses. In the auditory cortex, synaptic zinc modulates sound frequency tuning and enhances frequency discrimination acuity. In auditory, visual, and somatosensory circuits, sensory experience causes long-term changes in synaptic zinc levels and/or signaling, termed here synaptic zinc plasticity. However, the mechanisms underlying synaptic zinc plasticity and the effects of this plasticity on long-term glutamatergic plasticity remain unknown. To study these mechanisms, we used male and female mice and employed in vitro and in vivo models in zinc-rich, glutamatergic dorsal cochlear nucleus (DCN) parallel fiber (PF) synapses. High-frequency stimulation of DCN PF synapses induced long-term depression of synaptic zinc signaling (Z-LTD), as evidenced by reduced zinc-mediated inhibition of AMPA receptor (AMPAR) excitatory postsynaptic currents (EPSCs). Low-frequency stimulation induced long-term potentiation of synaptic zinc signaling (Z-LTP), as evidenced by enhanced zinc-mediated inhibition of AMPAR EPSCs. Thus, Z-LTD is a new mechanism of LTP and Z-LTD is a new mechanism of LTP. Pharmacological inhibition of Group 1 metabotropic glutamate receptors (G1 mGluRs) eliminated Z-LTD and Z-LTP. Pharmacological activation of G1 mGluRs induced Z-LTD and Z-LTP, associated with bidirectional changes in presynaptic zinc levels. Finally, exposure of mice to loud sound caused G1 mGluR-dependent Z-LTD in DCN PF synapses, consistent with our in vitro results. Together, we show that G1 mGluR activation is necessary and sufficient for inducing bidirectional long-term synaptic zinc plasticity.Key points summarySynaptic zinc is coreleased with glutamate to modulate neurotransmission and auditory processing. Sensory experience causes long-term changes in synaptic zinc signaling, termed synaptic zinc plasticity.At zinc-containing glutamatergic synapses in the dorsal cochlear nucleus (DCN), we show that high-frequency stimulation reduces synaptic zinc signaling (Z-LTD), whereas low-frequency stimulation increases synaptic zinc signaling (Z-LTP).Group 1 metabotropic glutamate receptor (mGluR) activation is necessary and sufficient to induce Z-LTP and Z-LTD. Z-LTP and Z-LTD are associated with bidirectional changes in presynaptic zinc levels.Sound-induced Z-LTD at DCN synapses requires Group 1 mGluR activation.Bidirectional synaptic zinc plasticity is a previously unknown mechanism of LTP and LTD at zinc-containing glutamatergic synapses.