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1. The Astrocytic Zinc Transporter ZIP12 Is a Synaptic Protein That Contributes to Synaptic Zinc Levels in the Mouse Auditory Cortex

   https://doi.org/10.1523/JNEUROSCI.2067-24.2025  

   Manning, Abbey; Mendelson, Benjamin_Z; Bender, Philip_T_R; Bainer, Kaitlin; Ruby, Rayli; Shifflett, Victoria_R; Dariano, 3rd, Donald_F; Webb, Bradley_A; Geldenhuys, Werner_J; Anderson, Charles_T (January 2025, The Journal of Neuroscience)

   Synaptically released zinc is a neuronal signaling system that arises from the actions of the presynaptic vesicular zinc transporter protein zinc transporter 3 (ZnT3). Mechanisms that regulate the actions of zinc at synapses are of great importance for many aspects of synaptic signaling in the brain. Here, we identify the astrocytic zinc transporter protein ZIP12 as a candidate mechanism that contributes to zinc clearance at cortical synapses. We identify small-molecule compounds that antagonize the function of ZIP12 in heterologous expression systems, and we use one of these compounds, ZIP12 modulator 8, to increase the concentration of ZnT3-dependent zinc at synapses in the brain of male and female mice to inhibit the activity of neuronal AMPA and NMDA glutamate receptors. These results identify a cellular mechanism and provide a pharmacological toolbox to target the molecular machinery that supports the actions of synaptic zinc in the brain. 

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2. Basal lamina: A novel pH regulator at the neuromuscular junction

   https://doi.org/10.1177/00368504231225066  

   Durbin, Ryan; Renden, Robert (January 2024, Science Progress)

   Proton concentration can change within the cleft during synaptic activity due to vesicular release and Ca²⁺extrusion from cellular compartments. These changes within the synaptic cleft can impact neural activity by proton-dependent modulation of ion channel function. The pH transient differs in magnitude and direction between synapses, requiring different synapse types to be measured to generate a complete understanding of this mechanism and its impacts on physiology. With a focus on the mouse neuromuscular junction (NMJ), the recently published “Postsynaptic Calcium Extrusion at the Mouse Neuromuscular Junction Alkalinizes the Synaptic Cleft” measured synaptic cleft pH at a cholinergic synapse and found a biphasic pH transient. The study demonstrated that the changes in proton concentration found were due to postsynaptic signaling when measuring pH at the muscle membrane, despite the expectation of a presynaptic contribution. This result suggests a diffusional barrier within the NMJ isolates pH transients to presynaptic versus postsynaptic compartments. Generating a Donnan equilibrium that impacts protons, evidence suggests the basal lamina may be a key regulator of pH at the NMJ. Exploring synaptic pH, proton regulating factors, and downstream pH transient effects at presynaptic versus postsynaptic membranes may lead to new insight for a variety of diseases. 

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3. Synaptic zinc inhibition of NMDA receptors depends on the association of GluN2A with the zinc transporter ZnT1

   https://doi.org/10.1126/sciadv.abb1515  

   Krall, Rebecca F.; Moutal, Aubin; Phillips, Matthew B.; Asraf, Hila; Johnson, Jon W.; Khanna, Rajesh; Hershfinkel, Michal; Aizenman, Elias; Tzounopoulos, Thanos (July 2020, Science Advances)

   The NMDA receptor (NMDAR) is inhibited by synaptically released zinc. This inhibition is thought to be the result of zinc diffusion across the synaptic cleft and subsequent binding to the extracellular domain of the NMDAR. However, this model fails to incorporate the observed association of the highly zinc-sensitive NMDAR subunit GluN2A with the postsynaptic zinc transporter ZnT1, which moves intracellular zinc to the extracellular space. Here, we report that disruption of ZnT1-GluN2A association by a cell-permeant peptide strongly reduced NMDAR inhibition by synaptic zinc in mouse dorsal cochlear nucleus synapses. Moreover, synaptic zinc inhibition of NMDARs required postsynaptic intracellular zinc, suggesting that cytoplasmic zinc is transported by ZnT1 to the extracellular space in close proximity to the NMDAR. These results challenge a decades-old dogma on how zinc inhibits synaptic NMDARs and demonstrate that presynaptic release and a postsynaptic transporter organize zinc into distinct microdomains to modulate NMDAR neurotransmission. 

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4. Presynaptic endoplasmic reticulum regulates short-term plasticity in hippocampal synapses

   https://doi.org/10.1038/s42003-021-01761-7  

   Singh, Nishant; Bartol, Thomas; Levine, Herbert; Sejnowski, Terrence; Nadkarni, Suhita (December 2021, Communications Biology)

   null (Ed.)

   Abstract Short-term plasticity preserves a brief history of synaptic activity that is communicated to the postsynaptic neuron. This is primarily regulated by a calcium signal initiated by voltage dependent calcium channels in the presynaptic terminal. Imaging studies of CA3-CA1 synapses reveal the presence of another source of calcium, the endoplasmic reticulum (ER) in all presynaptic terminals. However, the precise role of the ER in modifying STP remains unexplored. We performed in-silico experiments in synaptic geometries based on reconstructions of the rat CA3-CA1 synapses to investigate the contribution of ER. Our model predicts that presynaptic ER is critical in generating the observed short-term plasticity profile of CA3-CA1 synapses and allows synapses with low release probability to operate more reliably. Blocking the ER lowers facilitation in a manner similar to what has been previously characterized in animal models of Alzheimer’s disease and underscores the important role played by presynaptic stores in normal function. 

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5. Postsynaptic receptors regulate presynaptic transmitter stability through transsynaptic bridges

   https://doi.org/10.1073/pnas.2318041121  

   Godavarthi, Swetha K.; Hiramoto, Masaki; Ignatyev, Yuri; Levin, Jacqueline B.; Li, Hui-quan; Pratelli, Marta; Borchardt, Jennifer; Czajkowski, Cynthia; Borodinsky, Laura N.; Sweeney, Lora; et al (April 2024, Proceedings of the National Academy of Sciences)

   NA (Ed.)

   Stable matching of neurotransmitters with their receptors is fundamental to synapse function and reliable communication in neural circuits. Presynaptic neurotransmitters regulate the stabilization of postsynaptic transmitter receptors. Whether postsynaptic receptors regulate stabilization of presynaptic transmitters has received less attention. Here, we show that blockade of endogenous postsynaptic acetylcholine receptors (AChR) at the neuromuscular junction destabilizes the cholinergic phenotype in motor neurons and stabilizes an earlier, developmentally transient glutamatergic phenotype. Further, expression of exogenous postsynaptic gamma-aminobutyric acid type A receptors (GABA_Areceptors) in muscle cells stabilizes an earlier, developmentally transient GABAergic motor neuron phenotype. Both AChR and GABA_Areceptors are linked to presynaptic neurons through transsynaptic bridges. Knockdown of specific components of these transsynaptic bridges prevents stabilization of the cholinergic or GABAergic phenotypes. Bidirectional communication can enforce a match between transmitter and receptor and ensure the fidelity of synaptic transmission. Our findings suggest a potential role of dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter. 

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