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1. 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. 

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2. Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus)

   https://doi.org/10.3389/fnagi.2023.1146245  

   Glavis-Bloom, Courtney; Vanderlip, Casey R.; Weiser Novak, Sammy; Kuwajima, Masaaki; Kirk, Lyndsey; Harris, Kristen M.; Manor, Uri; Reynolds, John H. (April 2023, Frontiers in Aging Neuroscience)

   Morphology and function of the dorsolateral prefrontal cortex (dlPFC), and corresponding working memory performance, are affected early in the aging process, but nearly half of aged individuals are spared of working memory deficits. Translationally relevant model systems are critical for determining the neurobiological drivers of this variability. The common marmoset (Callithrix jacchus) is advantageous as a model for these investigations because, as a non-human primate, marmosets have a clearly defined dlPFC that enables measurement of prefrontal-dependent cognitive functions, and their short (∼10 year) lifespan facilitates longitudinal studies of aging. Previously, we characterized working memory capacity in a cohort of marmosets that collectively covered the lifespan, and found age-related working memory impairment. We also found a remarkable degree of heterogeneity in performance, similar to that found in humans. Here, we tested the hypothesis that changes to synaptic ultrastructure that affect synaptic efficacy stratify marmosets that age with cognitive impairment from those that age without cognitive impairment. We utilized electron microscopy to visualize synapses in the marmoset dlPFC and measured the sizes of boutons, presynaptic mitochondria, and synapses. We found that coordinated scaling of the sizes of synapses and mitochondria with their associated boutons is essential for intact working memory performance in aged marmosets. Further, lack of synaptic scaling, due to a remarkable failure of synaptic mitochondria to scale with presynaptic boutons, selectively underlies age-related working memory impairment. We posit that this decoupling results in mismatched energy supply and demand, leading to impaired synaptic transmission. We also found that aged marmosets have fewer synapses in dlPFC than young, though the severity of synapse loss did not predict whether aging occurred with or without cognitive impairment. This work identifies a novel mechanism of synapse dysfunction that stratifies marmosets that age with cognitive impairment from those that age without cognitive impairment. The process by which synaptic scaling is regulated is yet unknown and warrants future investigation. 

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3. Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission

   https://doi.org/10.1016/j.celrep.2024.114186  

   Cuhadar, Ulku; Calzado-Reyes, Lorenzo; Pascual-Caro, Carlos; Aberra, Aman S; Ritzau-Jost, Andreas; Aggarwal, Abhi; Ibata, Keiji; Podgorski, Kaspar; Yuzaki, Michisuke; Geis, Christian; et al (May 2024, Cell Reports)

   The fine control of synaptic function requires robust trans-synaptic molecular interactions. However, it remains poorly understood how trans-synaptic bridges change to reflect the functional states of the synapse. Here, we develop optical tools to visualize in firing synapses the molecular behavior of two trans-synaptic proteins, LGI1 and ADAM23, and find that neuronal activity acutely rearranges their abundance at the synaptic cleft. Surprisingly, synaptic LGI1 is primarily not secreted, as described elsewhere, but exo- and endocytosed through its interaction with ADAM23. Activity-driven translocation of LGI1 facilitates the formation of trans-synaptic connections proportionally to the history of activity of the synapse, adjusting excitatory transmission to synaptic firing rates. Accordingly, we find that patient-derived autoantibodies against LGI1 reduce its surface fraction and cause increased glutamate release. Our findings suggest that LGI1 abundance at the synaptic cleft can be acutely remodeled and serves as a critical control point for synaptic function. 

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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. Neuromuscular Active Zone Structure and Function in Healthy and Lambert-Eaton Myasthenic Syndrome States

   https://doi.org/10.3390/biom12060740  

   Ginebaugh, Scott P; Badawi, Yomna; Tarr, Tyler B; Meriney, Stephen D (June 2022, Biomolecules)

   The mouse neuromuscular junction (NMJ) has long been used as a model synapse for the study of neurotransmission in both healthy and disease states of the NMJ. Neurotransmission from these neuromuscular nerve terminals occurs at highly organized structures called active zones (AZs). Within AZs, the relationships between the voltage-gated calcium channels and docked synaptic vesicles govern the probability of acetylcholine release during single action potentials, and the short-term plasticity characteristics during short, high frequency trains of action potentials. Understanding these relationships is important not only for healthy synapses, but also to better understand the pathophysiology of neuromuscular diseases. In particular, we are interested in Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disorder in which neurotransmitter release from the NMJ decreases, leading to severe muscle weakness. In LEMS, the reduced neurotransmission is traditionally thought to be caused by the antibody-mediated removal of presynaptic voltage-gated calcium channels. However, recent experimental data and AZ computer simulations have predicted that a disruption in the normally highly organized active zone structure, and perhaps autoantibodies to other presynaptic proteins, contribute significantly to pathological effects in the active zone and the characteristics of chemical transmitters. 

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