Mechanisms Underlying Long-Term Synaptic Zinc Plasticity at Mouse Dorsal Cochlear Nucleus Glutamatergic Synapses.

In many brain areas, such as the neocortex, limbic structures, and auditory brainstem, synaptic zinc is released from presynaptic terminals to modulate neurotransmission. As such, synaptic zinc signaling modulates sensory processing and enhances acuity for discrimination of different sensory stimuli. Whereas sensory experience causes long-term changes in synaptic zinc signaling, the mechanisms underlying this long-term synaptic zinc plasticity remain unknown. To study these mechanisms in male and female mice, we used in vitro and in vivo models of zinc plasticity observed at the zinc-rich glutamatergic dorsal cochlear nucleus (DCN) parallel fiber synapses onto cartwheel cells. High-frequency stimulation of DCN parallel fiber synapses induced LTD of synaptic zinc signaling (Z-LTD), evidenced by reduced zinc-mediated inhibition of EPSCs. Low-frequency stimulation induced LTP of synaptic zinc signaling (Z-LTP), evidenced by enhanced zinc-mediated inhibition of EPSCs. Pharmacological manipulations of Group 1 metabotropic glutamate receptors (G1 mGluRs) demonstrated that G1 mGluR activation is necessary and sufficient for inducing Z-LTD and Z-LTP. Pharmacological manipulations of Ca2+ dynamics indicated that rises in postsynaptic Ca2+ are necessary and sufficient for Z-LTD induction. Electrophysiological measurements assessing postsynaptic expression mechanisms, and imaging studies with a ratiometric extracellular zinc sensor probing zinc release, supported that Z-LTD is expressed, at least in part, via reductions in presynaptic zinc release. Finally, exposure of mice to loud sound caused G1 mGluR-dependent Z-LTD at DCN parallel fiber synapses, thus validating our in vitro results. Together, our results reveal a novel mechanism underlying activity- and experience-dependent plasticity of synaptic zinc signaling.SIGNIFICANCE STATEMENT In the neocortex, limbic structures, and auditory brainstem, glutamatergic nerve terminals corelease zinc to modulate excitatory neurotransmission and sensory responses. Moreover, sensory experience causes bidirectional, long-term changes in synaptic zinc signaling. However, the mechanisms of this long-term synaptic zinc plasticity remain unknown. Here, we identified a novel Group 1 mGluR-dependent mechanism that causes bidirectional, long-term changes in synaptic zinc signaling. Our results highlight new mechanisms of brain adaptation during sensory processing, and potentially point to mechanisms of disorders associated with pathologic adaptation, such as tinnitus.

Differential inhibition of pyramidal cells and inhibitory interneurons along the rostrocaudal axis of anterior piriform cortex.

The spatial representation of stimuli in sensory neocortices provides a scaffold for elucidating circuit mechanisms underlying sensory processing. However, the anterior piriform cortex (APC) lacks topology for odor identity as well as afferent and intracortical excitation. Consequently, olfactory processing is considered homogenous along the APC rostral-caudal (RC) axis. We recorded excitatory and inhibitory neurons in APC while optogenetically activating GABAergic interneurons along the RC axis. In contrast to excitation, we find opposing, spatially asymmetric inhibition onto pyramidal cells (PCs) and interneurons. PCs are strongly inhibited by caudal stimulation sites, whereas interneurons are strongly inhibited by rostral sites. At least two mechanisms underlie spatial asymmetries. Enhanced caudal inhibition of PCs is due to increased synaptic strength, whereas rostrally biased inhibition of interneurons is mediated by increased somatostatin-interneuron density. Altogether, we show differences in rostral and caudal inhibitory circuits in APC that may underlie spatial variation in odor processing along the RC axis.

Photoactivatable Sensors for Detecting Mobile Zinc.

Fluorescent sensors for mobile zinc are valuable for studying complex biological systems. Because these sensors typically bind zinc rapidly and tightly, there has been little temporal control over the activity of the probe after its application to a sample. The ability to control the activity of a zinc sensor in vivo during imaging experiments would greatly improve the time resolution of the measurement. Here, we describe photoactivatable zinc sensors that can be triggered with short pulses of UV light. These probes are prepared by functionalizing a zinc sensor with protecting groups that render the probe insensitive to metal ions. Photoinduced removal of the protecting groups restores the binding site, allowing for zinc-responsive changes in fluorescence that can be observed in live cells and tissues.

Balanced feedforward inhibition and dominant recurrent inhibition in olfactory cortex.

Throughout the brain, the recruitment of feedforward and recurrent inhibition shapes neural responses. However, disentangling the relative contributions of these often-overlapping cortical circuits is challenging. The piriform cortex provides an ideal system to address this issue because the interneurons responsible for feedforward and recurrent inhibition are anatomically segregated in layer (L) 1 and L2/3 respectively. Here we use a combination of optical and electrical activation of interneurons to profile the inhibitory input received by three classes of principal excitatory neuron in the anterior piriform cortex. In all classes, we find that L1 interneurons provide weaker inhibition than L2/3 interneurons. Nonetheless, feedforward inhibitory strength covaries with the amount of afferent excitation received by each class of principal neuron. In contrast, intracortical stimulation of L2/3 evokes strong inhibition that dominates recurrent excitation in all classes. Finally, we find that the relative contributions of feedforward and recurrent pathways differ between principal neuron classes. Specifically, L2 neurons receive more reliable afferent drive and less overall inhibition than L3 neurons. Alternatively, L3 neurons receive substantially more intracortical inhibition. These three features--balanced afferent drive, dominant recurrent inhibition, and differential recruitment by afferent vs. intracortical circuits, dependent on cell class--suggest mechanisms for olfactory processing that may extend to other sensory cortices.