More Like this

1. 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. 

   more » « less
2. Neuronal Glutamatergic Synaptic Clefts Alkalinize Rather Than Acidify during Neurotransmission

   https://doi.org/10.1523/jneurosci.1774-19.2020  

   Stawarski, Michal; Hernandez, Roberto X; Feghhi, Touhid; Borycz, Jolanta A; Lu, Zhiyuan; Agarwal, Andrea B; Reihl, Kelly D; Tavora, Rubens; Lau, AWC; Meinertzhagen, Ian A; et al (February 2020, The Journal of Neuroscience)

   The dogma that the synaptic cleft acidifies during neurotransmission is based on the corelease of neurotransmitters and protons from synaptic vesicles, and is supported by direct data from sensory ribbon-type synapses. However, it is unclear whether acidification occurs at non–ribbon-type synapses. Here we used genetically encoded fluorescent pH indicators to examine cleft pH at conventional neuronal synapses. At the neuromuscular junction of femaleDrosophilalarvae, we observed alkaline spikes of over 1 log unit during fictive locomotionin vivo. Ex vivo, single action potentials evoked alkalinizing pH transients of only ∼0.01 log unit, but these transients summated rapidly during burst firing. A chemical pH indicator targeted to the cleft corroborated these findings. Cleft pH transients were dependent on Ca²⁺movement across the postsynaptic membrane, rather than neurotransmitter release per se, a result consistent with cleft alkalinization being driven by the Ca²⁺/H⁺antiporting activity of the plasma membrane Ca²⁺-ATPase at the postsynaptic membrane. Targeting the pH indicators to the microenvironment of the presynaptic voltage gated Ca²⁺channels revealed that alkalinization also occurred within the cleft proper at the active zone and not just within extrasynaptic regions. Application of the pH indicators at the mouse calyx of Held, a mammalian central synapse, similarly revealed cleft alkalinization during burst firing in both males and females. These findings, made at two quite different non–ribbon type synapses, suggest that cleft alkalinization during neurotransmission, rather than acidification, is a generalizable phenomenon across conventional neuronal synapses. SIGNIFICANCE STATEMENTNeurotransmission is highly sensitive to the pH of the extracellular milieu. This is readily evident in the neurological symptoms that accompany systemic acid/base imbalances. Imaging data from sensory ribbon-type synapses show that neurotransmission itself can acidify the synaptic cleft, likely due to the corelease of protons and glutamate. It is not clear whether the same phenomenon occurs at conventional neuronal synapses due to the difficulties in collecting such data. If it does occur, it would provide for an additional layer of activity-dependent modulation of neurotransmission. Our findings of alkalinization, rather than acidification, within the cleft of two different neuronal synapses encourages a reassessment of the scope of activity-dependent pH influences on neurotransmission and short-term synaptic plasticity. 

   more » « less
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. 

   more » « less
4. The C. elegans uv1 Neuroendocrine Cells Provide Mechanosensory Feedback of Vulval Opening

   https://doi.org/10.1523/JNEUROSCI.0678-24.2024  

   Yan, Lijie; Claman, Alexander; Bode, Addys; Collins, Kevin M (February 2025, The Journal of Neuroscience)

   Neuroendocrine cells react to physical, chemical, and synaptic signals originating from tissues and the nervous system, releasing hormones that regulate various body functions beyond the synapse. Neuroendocrine cells are often embedded in complex tissues making direct tests of their activation mechanisms and signaling effects difficult to study. In the nematode wormCaenorhabditis elegans, four uterine-vulval (uv1) neuroendocrine cells sit above the vulval canal next to the egg-laying circuit, releasing tyramine and neuropeptides that feedback to inhibit egg laying. We have previously shown uv1 cells are mechanically deformed during egg laying, driving uv1 Ca²⁺transients. However, whether egg-laying circuit activity, vulval opening, and/or egg release triggered uv1 Ca²⁺activity was unclear. Here, we show uv1 responds directly to mechanical activation. Optogenetic vulval muscle stimulation triggers uv1 Ca²⁺activity following muscle contraction even in sterile animals. Direct mechanical prodding with a glass probe placed against the worm cuticle triggers robust uv1 Ca²⁺activity similar to that seen during egg laying. Direct mechanical activation of uv1 cells does not require other cells in the egg-laying circuit, synaptic or peptidergic neurotransmission, or transient receptor potential vanilloid and Piezo channels. EGL-19 L-type Ca²⁺channels, but not P/Q/N-type or ryanodine receptor Ca²⁺channels, promote uv1 Ca²⁺activity following mechanical activation. L-type channels also facilitate the coordinated activation of uv1 cells across the vulva, suggesting mechanical stimulation of one uv1 cell cross-activates the other. Our findings show how neuroendocrine cells like uv1 report on the mechanics of tissue deformation and muscle contraction, facilitating feedback to local circuits to coordinate behavior. 

   more » « less
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. 

   more » « less