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Open accessJournal ArticleDOI: 10.1073/PNAS.2016754118

Rapid Ca2+ channel accumulation contributes to cAMP-mediated increase in transmission at hippocampal mossy fiber synapses

02 Mar 2021-Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences)-Vol. 118, Iss: 9
Abstract: The cyclic adenosine monophosphate (cAMP)-dependent potentiation of neurotransmitter release is important for higher brain functions such as learning and memory. To reveal the underlying mechanisms, we applied paired pre- and postsynaptic recordings from hippocampal mossy fiber-CA3 synapses. Ca2+ uncaging experiments did not reveal changes in the intracellular Ca2+ sensitivity for transmitter release by cAMP, but suggested an increase in the local Ca2+ concentration at the release site, which was much lower than that of other synapses before potentiation. Total internal reflection fluorescence (TIRF) microscopy indicated a clear increase in the local Ca2+ concentration at the release site within 5 to 10 min, suggesting that the increase in local Ca2+ is explained by the simple mechanism of rapid Ca2+ channel accumulation. Consistently, two-dimensional time-gated stimulated emission depletion microscopy (gSTED) microscopy showed an increase in the P/Q-type Ca2+ channel cluster size near the release sites. Taken together, this study suggests a potential mechanism for the cAMP-dependent increase in transmission at hippocampal mossy fiber-CA3 synapses, namely an accumulation of active zone Ca2+ channels.

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Topics: Hippocampal mossy fiber (65%), Active zone (54%), Long-term potentiation (53%) ... read more
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5 results found


Open accessJournal ArticleDOI: 10.1371/JOURNAL.PONE.0253642
Nicholas P. Vyleta1, Jason S. Snyder1Institutions (1)
18 Jun 2021-PLOS ONE
Abstract: Critical period plasticity at adult-born neuron synapses is widely believed to contribute to the learning and memory functions of the hippocampus. Experience regulates circuit integration and for a transient interval, until cells are ~6 weeks old, new neurons display enhanced long-term potentiation (LTP) at afferent and efferent synapses. Since neurogenesis declines substantially with age, this raises questions about the extent of lasting plasticity offered by adult-born neurons. Notably, however, the hippocampus receives sensory information from two major cortical pathways. Broadly speaking, the medial entorhinal cortex conveys spatial information to the hippocampus via the medial perforant path (MPP), and the lateral entorhinal cortex, via the lateral perforant path (LPP), codes for the cues and items that make experiences unique. While enhanced critical period plasticity at MPP synapses is relatively well characterized, no studies have examined long-term plasticity at LPP synapses onto adult-born neurons, even though the lateral entorhinal cortex is uniquely vulnerable to aging and Alzheimer's pathology. We therefore investigated LTP at LPP inputs both within (4-6 weeks) and beyond (8+ weeks) the traditional critical period. At immature stages, adult-born neurons did not undergo significant LTP at LPP synapses, and often displayed long-term depression after theta burst stimulation. However, over the course of 3-4 months, adult-born neurons displayed increasingly greater amounts of LTP. Analyses of short-term plasticity point towards a presynaptic mechanism, where transmitter release probability declines as cells mature, providing a greater dynamic range for strengthening synapses. Collectively, our findings identify a novel form of new neuron plasticity that develops over an extended interval, and may therefore be relevant for maintaining cognitive function in aging.

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Topics: Entorhinal cortex (61%), Perforant path (59%), Hippocampus (57%) ... read more

2 Citations


Open accessPosted ContentDOI: 10.1101/2021.09.06.459077
06 Sep 2021-bioRxiv
Abstract: The performance of available optogenetic inhibitors remains insufficient due to low light sensitivity, short-lasting photocurrents, and unintended changes in ion distributions. To overcome these limitations, a novel potassium channel-based optogenetic silencer was developed and successfully applied in various in vitro and acute in vivo settings (Bernal Sierra et al., 2018). This tool, a two-component construct called PACK, comprises a photoactivated adenylyl cyclase (bPAC) and a cAMP-dependent potassium channel (SthK). Here, we examined the long-term inhibitory action and side effects of the PACK construct in healthy and epileptic adult male mice. We targeted hippocampal CA1 pyramidal cells using a viral vector and enabled illumination of these neurons via an implanted optic fiber. Local field potential (LFP) recordings from the CA1 of freely moving mice revealed significantly reduced neuronal activity during 50-minute intermittent illumination, especially in the beta and gamma frequency ranges. Adversely, PACK expression in healthy mice induced chronic astrogliosis, dispersion of pyramidal cells, and generalized seizures. These side effects were independent of the light application and were also present in mice expressing bPAC without the potassium channel. Additionally, light-activation of bPAC alone increased neuronal activity, presumably via enhanced cAMP signaling. In chronically epileptic mice, the dark activity of bPAC/PACK in CA1 prevented the spread of spontaneous epileptiform activity from the seizure focus to the contralateral bPAC/PACK-expressing hippocampus. Taken together, the PACK tool is a potent optogenetic inhibitor but requires refinement of its light-sensitive domain to avoid unexpected physiological changes.

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Topics: Potassium channel (51%), Optogenetics (50%)

Open accessPosted ContentDOI: 10.1101/2021.03.15.435460
Nicholas P. Vyleta1, Jason S. Snyder1Institutions (1)
15 Mar 2021-bioRxiv
Abstract: Critical period plasticity at adult-born neuron synapses is widely believed to contribute to the learning and memory functions of the hippocampus. Experience regulates circuit integration and for a transient interval, until cells are ~6 weeks old, new neurons display enhanced long-term potentiation (LTP) at afferent and efferent synapses. Since neurogenesis declines substantially with age, this raises questions about the extent of lasting plasticity offered by adult-born neurons. Notably, however, the hippocampus receives sensory information from two major cortical pathways. Broadly speaking, the medial entorhinal cortex conveys spatial information to the hippocampus via the medial perforant path (MPP), and the lateral entorhinal cortex, via the lateral perforant path (LPP), codes for the cues and items that make experiences unique. While enhanced critical period plasticity at MPP synapses is relatively well characterized, no studies have examined long-term plasticity at LPP synapses onto adult-born neurons, even though the lateral entorhinal cortex is uniquely vulnerable to aging and Alzheimer’s pathology. We therefore investigated LTP at LPP inputs both within (4-6 weeks) and beyond (8+ weeks) the traditional critical period. At immature stages, adult-born neurons did not undergo significant LTP at LPP synapses, and often displayed long-term depression after theta burst stimulation. However, over the course of 3-4 months, adult-born neurons displayed increasingly greater amounts of LTP. Analyses of short-term plasticity point towards a presynaptic mechanism, where transmitter release probability declines as cells mature, providing a greater dynamic range for strengthening synapses. Collectively, our findings identify a novel form of new neuron plasticity that develops over an extended interval, and may therefore be relevant for maintaining cognitive function in aging.

... read more

Topics: Entorhinal cortex (61%), Perforant path (59%), Hippocampus (57%) ... read more

Open accessJournal ArticleDOI: 10.7554/ELIFE.70408
06 Oct 2021-eLife
Abstract: The Ca2+-dependence of the priming, fusion, and replenishment of synaptic vesicles are fundamental parameters controlling neurotransmitter release and synaptic plasticity. Despite intense efforts, these important steps in the synaptic vesicles' cycle remain poorly understood due to the technical challenge in disentangling vesicle priming, fusion, and replenishment. Here, we investigated the Ca2+-sensitivity of these steps at mossy fiber synapses in the rodent cerebellum, which are characterized by fast vesicle replenishment mediating high-frequency signaling. We found that the basal free Ca2+ concentration (<200 nM) critically controls action potential-evoked release, indicating a high-affinity Ca2+ sensor for vesicle priming. Ca2+ uncaging experiments revealed a surprisingly shallow and non-saturating relationship between release rate and intracellular Ca2+ concentration up to 50 μM. The rate of vesicle replenishment during sustained elevated intracellular Ca2+ concentration exhibited little Ca2+-dependence. Finally, quantitative mechanistic release schemes with five Ca2+ binding steps incorporating rapid vesicle replenishment via parallel or sequential vesicle pools could explain our data. We thus show that co-existing high- and low-affinity Ca2+ sensors mediate priming, fusion, and replenishment of synaptic vesicles at a high-fidelity synapse.

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Topics: Vesicle fusion (62%), Synaptic vesicle (59%), Vesicle (54%) ... read more

Open accessPosted ContentDOI: 10.1101/2021.05.15.444285
17 May 2021-bioRxiv
Abstract: The Ca2+-dependence of the recruitment, priming, and fusion of synaptic vesicles are fundamental parameters controlling neurotransmitter release and synaptic plasticity. Despite intense efforts, these important steps in the synaptic vesicles’ cycle remain poorly understood because disentangling recruitment, priming, and fusion of vesicles is technically challenging. Here, we investigated the Ca2+-sensitivity of these steps at cerebellar mossy fiber synapses, which are characterized by fast vesicle recruitment mediating high-frequency signaling. We found that the basal free Ca2+ concentration (

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Topics: Synaptic vesicle (62%), Cerebellar mossy fiber (61%), Synaptic plasticity (57%) ... read more
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69 results found


Robert S. Zucker1, Wade G. Regehr2Institutions (2)
Abstract: ▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

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Topics: Synaptic augmentation (69%), Chemical synaptic transmission (68%), Neural facilitation (65%) ... read more

4,233 Citations


Journal ArticleDOI: 10.1126/SCIENCE.1067020
Eric R. Kandel1Institutions (1)
02 Nov 2001-Science
Abstract: One of the most remarkable aspects of an animal's behavior is the ability to modify that behavior by learning, an ability that reaches its highest form in human beings. For me, learning and memory have proven to be endlessly fascinating mental processes because they address one of the fundamental features of human activity: our ability to acquire new ideas from experience and to retain these ideas over time in memory. Moreover, unlike other mental processes such as thought, language, and consciousness, learning seemed from the outset to be readily accessible to cellular and molecular analysis. I, therefore, have been curious to know: What changes in the brain when we learn? And, once something is learned, how is that information retained in the brain? I have tried to address these questions through a reductionist approach that would allow me to investigate elementary forms of learning and memory at a cellular molecular level-as specific molecular activities within identified nerve cells.

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Topics: Intermediate-term memory (53%)

3,403 Citations


Journal ArticleDOI: 10.1038/NRN1074
Martin Heisenberg1Institutions (1)
Abstract: Genetic intervention in the fly Drosophila melanogaster has provided strong evidence that the mushroom bodies of the insect brain act as the seat of a memory trace for odours. This localization gives the mushroom bodies a place in a network model of olfactory memory that is based on the functional anatomy of the olfactory system. In the model, complex odour mixtures are assumed to be represented by activated sets of intrinsic mushroom body neurons. Conditioning renders an extrinsic mushroom-body output neuron specifically responsive to such a set. Mushroom bodies have a second, less understood function in the organization of the motor output. The development of a circuit model that also addresses this function might allow the mushroom bodies to throw light on the basic operating principles of the brain.

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Topics: Mushroom bodies (62%), Kenyon cell (59%)

1,088 Citations


Open accessJournal ArticleDOI: 10.1016/J.NEURON.2008.08.019
Erwin Neher1, Takeshi Sakaba1Institutions (1)
25 Sep 2008-Neuron
Abstract: The intracellular calcium concentration ([Ca 2+ ]) has important roles in the triggering of neurotransmitter release and the regulation of short-term plasticity (STP). Transmitter release is initiated by quite high concentrations within microdomains, while short-term facilitation is strongly influenced by the global buildup of "residual calcium." A global rise in [Ca 2+ ] also accelerates the recruitment of release-ready vesicles, thereby controlling the degree of short-term depression (STD) during sustained activity, as well as the recovery of the vesicle pool in periods of rest. We survey data that lead us to propose two distinct roles of [Ca 2+ ] in vesicle recruitment: one accelerating "molecular priming" (vesicle docking and the buildup of a release machinery), the other promoting the tight coupling between releasable vesicles and Ca 2+ channels. Such coupling is essential for rendering vesicles sensitive to short [Ca 2+ ] transients, generated during action potentials.

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Topics: Vesicle docking (61%), Vesicle (53%), Calcium in biology (53%) ... read more

751 Citations


Open accessJournal ArticleDOI: 10.1038/35022702
Ralf Schneggenburger1, Erwin Neher1Institutions (1)
24 Aug 2000-Nature
Abstract: Calcium-triggered fusion of synaptic vesicles and neurotransmitter release are fundamental signalling steps in the central nervous system It is generally assumed that fast transmitter release is triggered by elevations in intracellular calcium concentration ([Ca2+]i) to at least 100 µM near the sites of vesicle fusion1,2,3,4,5 For synapses in the central nervous system, however, there are no experimental estimates of this local [Ca2+]i signal Here we show, by using calcium ion uncaging in the large synaptic terminals of the calyx of Held, that step-like elevations to only 10 µM [Ca2+] i induce fast transmitter release, which depletes around 80% of a pool of available vesicles in less than 3 ms Kinetic analysis of transmitter release rates after [Ca2+]i steps revealed the rate constants for calcium binding and vesicle fusion These show that transient (around 05 ms) local elevations of [Ca2+]i to peak values as low as 25 µM can account for transmitter release during single presynaptic action potentials The calcium sensors for vesicle fusion are far from saturation at normal release probability This non-saturation, and the high intracellular calcium cooperativity in triggering vesicle fusion, make fast synaptic transmission very sensitive to modulation by changes in local [Ca2+]i

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Topics: Vesicle fusion (58%), Synaptic vesicle (57%), Calyx of Held (55%) ... read more

700 Citations