RT Journal Article SR Electronic T1 Context-Dependent Modulation of Excitatory Synaptic Strength by Synaptically Released Zinc JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0011-17.2017 DO 10.1523/ENEURO.0011-17.2017 A1 Bopanna I. Kalappa A1 Thanos Tzounopoulos YR 2017 UL http://www.eneuro.org/content/early/2017/02/15/ENEURO.0011-17.2017.abstract AB Synaptically released zinc inhibits baseline excitatory neurotransmission; however, the role of this neuromodulator on short-term plasticity during different levels of synaptic activity remains largely unknown. This lack of knowledge prevents our understanding of information transfer across zinc-releasing synapses, including 50% of excitatory synapses in cortical areas. We used in vitro electrophysiology in mouse brain slices and discovered that the effects of zinc on excitatory postsynaptic current (EPSC) amplitudes are context-dependent. At lower frequencies of activity, synaptically released zinc reduces EPSC amplitudes. In contrast, at higher stimulation frequencies and vesicular release probability (Pr), zinc inhibits EPSC amplitudes during the first few stimuli but leads to enhanced steady-state EPSC amplitudes during subsequent stimuli. This paradoxical enhancement is due to zinc-dependent potentiation of synaptic facilitation via the recruitment of endocannabinoid signaling. Synaptically released zinc is a modulator of excitatory short-term plasticity which shapes information transfer among excitatory synapses.Significance Statement: In many brain areas, including the neocortex, limbic structures, and the auditory brainstem, glutamatergic nerve terminals also contain zinc in their synaptic vesicles. Zinc is loaded into these vesicles by the zinc transporter 3 and is co-released with glutamate. Synaptically released zinc is an inhibitory neuromodulator in excitatory synapses, but the role of zinc in short-term plasticity remains unknown. Our results suggest that zinc shapes excitatory synaptic strength in a frequency- and activity level-dependent manner. Namely, during low vesicular release probability (Pr) and low-frequency stimulation zinc inhibits EPSCs; however, during higher Pr and prolonged presynaptic stimulation zinc enhances steady state EPSCs.