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1. A comparison of three different methods of eliciting rapid activity-dependent synaptic plasticity at the Drosophila NMJ

   https://doi.org/10.1371/journal.pone.0260553  

   Maldonado-Díaz, Carolina ; Vazquez, Mariam ; Marie, Bruno ( November 2021 , PLOS ONE)

   Kim, Hongkyun (Ed.)

   The Drosophila NMJ is a system of choice for investigating the mechanisms underlying the structural and functional modifications evoked during activity-dependent synaptic plasticity. Because fly genetics allows considerable versatility, many strategies can be employed to elicit this activity. Here, we compare three different stimulation methods for eliciting activity-dependent changes in structure and function at the Drosophila NMJ. We find that the method using patterned stimulations driven by a K+-rich solution creates robust structural modifications but reduces muscle viability, as assessed by resting potential and membrane resistance. We argue that, using this method, electrophysiological studies that consider the frequency of events, rather than their amplitude, are the only reliable studies. We contrast these results with the expression of CsChrimson channels and red-light stimulation at the NMJ, as well as with the expression of TRPA channels and temperature stimulation. With both these methods we observed reliable modifications of synaptic structures and consistent changes in electrophysiological properties. Indeed, we observed a rapid appearance of immature boutons that lack postsynaptic differentiation, and a potentiation of spontaneous neurotransmission frequency. Surprisingly, a patterned application of temperature changes alone is sufficient to provoke both structural and functional plasticity. In this context, temperature-dependent TRPA channel activation induces additional structural plasticity but no further increase in the frequency of spontaneous neurotransmission, suggesting an uncoupling of these mechanisms. 

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2. Novel types of frequency filtering in the lateral perforant path projections to dentate gyrus

   https://doi.org/10.1113/JP283012  

   Quintanilla, Julian ; Jia, Yousheng ; Lauterborn, Julie C. ; Pruess, Benedict S. ; Le, Aliza A. ; Cox, Conor D. ; Gall, Christine M. ; Lynch, Gary ; Gunn, Benjamin G. ( August 2022 , The Journal of Physiology)

   Despite its evident importance to learning theory and models, the manner in which the lateral perforant path (LPP) transforms signals from entorhinal cortex to hippocampus is not well understood. The present studies measured synaptic responses in the dentate gyrus (DG) of adult mouse hippocampal slices during different patterns of LPP stimulation. Theta (5 Hz) stimulation produced a modest within‐train facilitation that was markedly enhanced at the level of DG output. Gamma (50 Hz) activation resulted in a singular pattern with initial synaptic facilitation being followed by a progressively greater depression. DG output was absent after only two pulses. Reducing release probability with low extracellular calcium instated frequency facilitation to gamma stimulation while long‐term potentiation, which increases release by LPP terminals, enhanced within‐train depression. Relatedly, per terminal concentrations of VGLUT2, a vesicular glutamate transporter associated with high release probability, were much greater in the LPP than in CA3–CA1 connections. Attempts to circumvent the potent gamma filter using a series of short (three‐pulse) 50 Hz trains spaced by 200 ms were only partially successful: composite responses were substantially reduced after the first burst, an effect opposite to that recorded in field CA1. The interaction between bursts was surprisingly persistent (>1.0 s). Low calcium improved throughput during theta/gamma activation but buffering of postsynaptic calcium did not. In all, presynaptic specializations relating to release probability produce an unusual but potent type of frequency filtering in the LPP. Patterned burst input engages a different type of filter with substrates that are also likely to be located presynaptically.image

   The lateral perforant path (LPP)–dentate gyrus (DG) synapse operates as a low‐pass filter, where responses to a train of 50 Hz, γ frequency activation are greatly suppressed.

   Activation with brief bursts of γ frequency information engages a secondary filter that persists for prolonged periods (lasting seconds).

   Both forms of LPP frequency filtering are influenced by presynaptic, as opposed to postsynaptic, processes; this contrasts with other hippocampal synapses.

   LPP frequency filtering is modified by the unique presynaptic long‐term potentiation at this synapse.

   Computational simulations indicate that presynaptic factors associated with release probability and vesicle recycling may underlie the potent LPP–DG frequency filtering.

    

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3. 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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4. 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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5. Spike timing-dependent plasticity alters electrosensory neuron synaptic strength in vitro but does not consistently predict changes in sensory tuning in vivo

   https://doi.org/10.1152/jn.00498.2022  

   Lube, Adalee J. ; Ma, Xiaofeng ; Carlson, Bruce A. ( May 2023 , Journal of Neurophysiology)

   How do sensory systems optimize detection of behaviorally relevant stimuli when the sensory environment is constantly changing? We addressed the role of spike timing-dependent plasticity (STDP) in driving changes in synaptic strength in a sensory pathway and whether those changes in synaptic strength could alter sensory tuning. It is challenging to precisely control temporal patterns of synaptic activity in vivo and replicate those patterns in vitro in behaviorally relevant ways. This makes it difficult to make connections between STDP-induced changes in synaptic physiology and plasticity in sensory systems. Using the mormyrid species Brevimyrus niger and Brienomyrus brachyistius, which produce electric organ discharges for electrolocation and communication, we can precisely control the timing of synaptic input in vivo and replicate these same temporal patterns of synaptic input in vitro. In central electrosensory neurons in the electric communication pathway, using whole cell intracellular recordings in vitro, we paired presynaptic input with postsynaptic spiking at different delays. Using whole cell intracellular recordings in awake, behaving fish, we paired sensory stimulation with postsynaptic spiking using the same delays. We found that Hebbian STDP predictably alters sensory tuning in vitro and is mediated by NMDA receptors. However, the change in synaptic responses induced by sensory stimulation in vivo did not adhere to the direction predicted by the STDP observed in vitro. Further analysis suggests that this difference is influenced by polysynaptic activity, including inhibitory interneurons. Our findings suggest that STDP rules operating at identified synapses may not drive predictable changes in sensory responses at the circuit level. NEW & NOTEWORTHY We replicated behaviorally relevant temporal patterns of synaptic activity in vitro and used the same patterns during sensory stimulation in vivo. There was a Hebbian spike timing-dependent plasticity (STDP) pattern in vitro, but sensory responses in vivo did not shift according to STDP predictions. Analysis suggests that this disparity is influenced by differences in polysynaptic activity, including inhibitory interneurons. These results suggest that STDP rules at synapses in vitro do not necessarily apply to circuits in vivo. 

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