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Synaptotagmin 7 is shown to be essential for synaptic facilitation at a variety of central synapses, and the results pave the way for future functional studies of short-term synaptic plasticity, a fundamental form of neuronal computation. Synaptic facilitation requires synaptotagmin 7 Synaptic facilitation is a process — first observed more than 70 years ago — that allows neurons to dynamically regulate neurotransmitter release in an activity-dependent manner. It is manifest as short-term synaptic enhancement lasting for up to several hundred milliseconds. Wade Regehr and colleagues have now identified synaptotagmin 7 as the calcium sensor required for synaptic facilitation at a variety of central synapses. Previous studies had established a role for synaptotagmin 7 in the slow phase of transmission known as asynchronous release and in Ca 2+ -dependent recovery from depression. This result offers a key molecular handle for future functional studies of short-term synaptic plasticity, a fundamental form of neuronal computation. It has been known for more than 70 years that synaptic strength is dynamically regulated in a use-dependent manner 1 . At synapses with a low initial release probability, closely spaced presynaptic action potentials can result in facilitation, a short-term form of enhancement in which each subsequent action potential evokes greater neurotransmitter release 2 . Facilitation can enhance neurotransmitter release considerably and can profoundly influence information transfer across synapses 3 , but the underlying mechanism remains a mystery. One proposed mechanism is that a specialized calcium sensor for facilitation transiently increases the probability of release 2 , 4 , and this sensor is distinct from the fast sensors that mediate rapid neurotransmitter release. Yet such a sensor has never been identified, and its very existence has been disputed 5 , 6 . Here we show that synaptotagmin 7 (Syt7) is a calcium sensor that is required for facilitation at several central synapses. In Syt7-knockout mice, facilitation is eliminated even though the initial probability of release and the presynaptic residual calcium signals are unaltered. Expression of wild-type Syt7 in presynaptic neurons restored facilitation, whereas expression of a mutated Syt7 with a calcium-insensitive C2A domain did not. By revealing the role of Syt7 in synaptic facilitation, these results resolve a longstanding debate about a widespread form of short-term plasticity, and will enable future studies that may lead to a deeper understanding of the functional importance of facilitation.

The mechanisms of gliotransmitter release and their impact on neuronal signaling have remained largely elusive. The authors describe two functionally non-overlapping v-SNARE-dependent astrocytic release pathways that oppositely control synaptic strength at presynaptic sites. Thus, astrocytes are able to fine-tune fast glutamatergic neurotransmission and control fundamental processes of synaptic communication. Communication between glia cells and neurons is crucial for brain functions, but the molecular mechanisms and functional consequences of gliotransmission remain enigmatic. Here we report that astrocytes express synaptobrevin II and cellubrevin as functionally non-overlapping vesicular SNARE proteins on glutamatergic vesicles and neuropeptide Y-containing large dense-core vesicles, respectively. Using individual null-mutants for Vamp2 (synaptobrevin II) and Vamp3 (cellubrevin), as well as the corresponding compound null-mutant for genes encoding both v-SNARE proteins, we delineate previously unrecognized individual v-SNARE dependencies of astrocytic release processes and their functional impact on neuronal signaling. Specifically, we show that astroglial cellubrevin-dependent neuropeptide Y secretion diminishes synaptic signaling, while synaptobrevin II–dependent glutamate release from astrocytes enhances synaptic signaling. Our experiments thereby uncover the molecular mechanisms of two distinct v-SNARE-dependent astrocytic release pathways that oppositely control synaptic strength at presynaptic sites, elucidating new avenues of communication between astrocytes and neurons.

In the past 15 years numerous reports provided strong evidence that brain-derived neurotrophic factor (BDNF) is one of the most important modulators of glutamatergic and GABAergic synapses. Remarkable progress regarding localization, kinetics, and molecular mechanisms of BDNF secretion has been achieved, and a large number of studies provided evidence that continuous extracellular supply of BDNF is important for the proper formation and functional maturation of glutamatergic and GABAergic synapses. BDNF can play a permissive role in shaping synaptic networks, making them more susceptible for the occurrence of plastic changes. In addition, BDNF appears to be also an instructive factor for activity-dependent long-term synaptic plasticity. BDNF release just in response to synaptic stimulation might be a molecular trigger to convert high-frequency synaptic activity into long-term synaptic memories. This review attempts to summarize the current knowledge in synaptic secretion and synaptic action of BDNF, including both permissive and instructive effects of BDNF in synaptic plasticity.

Cell surface proteolysis is essential for communication between cells and results in the shedding of membrane‐protein ectodomains. However, physiological substrates of the contributing proteases are largely unknown. We developed the secretome protein enrichment with click sugars (SPECS) method, which allows proteome‐wide identification of shedding substrates and secreted proteins from primary cells, even in the presence of serum proteins. SPECS combines metabolic glycan labelling and click chemistry‐mediated biotinylation and distinguishes between cellular and serum proteins. SPECS identified 34, mostly novel substrates of the Alzheimer protease BACE1 in primary neurons, making BACE1 a major sheddase in the nervous system. Selected BACE1 substrates—seizure‐protein 6, L1, CHL1 and contactin‐2—were validated in brains of BACE1 inhibitor‐treated and BACE1 knock‐out mice. For some substrates, BACE1 was the major sheddase, whereas for other substrates additional proteases contributed to total substrate shedding. The new substrates point to a central function of BACE1 in neurite outgrowth and synapse formation. SPECS is also suitable for quantitative secretome analyses of primary cells and may be used for the discovery of biomarkers secreted from tumour or stem cells. BACE1 (β‐secretase) mediates plasma membrane shedding of the amyloid precursor protein (APP), the first step in the generation of A(β) peptide in Alzheimer's disease. A novel quantitative secretome technique identifies physiological substrates of BACE1, pointing to a central function of the protease in neurite outgrowth and synapse formation.

Key Points All synaptic vesicles are similar in terms of their ultrastructure and biochemistry, but for several decades investigators have proposed that there are 'pools' with distinct functional properties. These pools have been given a bewildering array of names, but this review proposes that each vesicle can be assigned to one of three pools: the readily releasable pool (RRP), the recycling pool and the reserve pool. Vesicle pools have been investigated in many systems, but five preparations have been characterized most thoroughly — Drosophila larval neuromuscular junction (NMJ), frog NMJ, neonatal rodent cultured hippocampal neurons, neonatal rodent calyx of held neurons and goldfish retinal bipolar cells. The RRP is defined as the synaptic vesicles that are immediately available on neural stimulation. These vesicles are generally thought to be docked to the presynaptic active zone and primed for release, although docked vesicles are not necessarily immediately releasable. The recycling pool is the pool of vesicles that maintain release on moderate stimulation. Physiological frequencies of stimulation cause it to recycle continuously, and it is refilled by newly recycled vesicles. The reserve pool is a depot of synaptic vesicles from which release is triggered only during intense stimulation. These vesicles constitute the majority of vesicles in most presynaptic terminals, and it is possible that they are seldom or never recruited during physiological activity. Traditionally, vesicle pools have been depicted as being morphologically segregated into distinct clusters, and the RRP must, by definition, lie at or close to the presynaptic membrane. However, recent evidence indicates that, at least in some preparations at least, vesicles in the recycling and reserve pools are intermixed to a considerable degree. It has been proposed that synapsin holds together the vesicles in the reserve pool, and that some kind of 'cage', perhaps consisting of actin, prevents the dispersal of recycling vesicles. However, it is also possible to visualize a model in which all vesicles are equally mobile, but only the recycling pool can exocytose efficiently on interaction with the active zone. It is proposed that recycling pool vesicles are generally retrieved through endocytosis directly from the plasma membrane, whereas reserve pool release is followed by bulk endocytosis. A fraction of the vesicles in mammalian systems might recycle through an ultrafast 'kiss-and-run' pathway, in which vesicles fuse transiently to the plasma membrane and reform by the closure of a fusion pore. Communication between cells reaches its highest degree of specialization at chemical synapses. Some synapses talk in a 'whisper'; others 'shout'. The 'louder' the synapse, the more synaptic vesicles are needed to maintain effective transmission, ranging from a few hundred (whisperers) to nearly a million (shouters). These vesicles reside in different 'pools', which have been given a bewildering array of names. In this review, we focus on five tissue preparations in which synaptic vesicle pools have been identified and thoroughly characterized. We argue that, in each preparation, each vesicle can be assigned to one of three distinct pools.

Significance Synapses with high probability of neurotransmitter release ( P ᵣ) depress during prolonged activity, which reduces the faithful transfer of information. Auditory nerve synapses onto bushy cells show particularly strong depression at physiologically relevant rates of activity, which raises the question of how bushy cells transmit information when sound levels are high for a prolonged period. After rearing mice in constant, nondamaging noise, auditory nerve synapses changed from high to low P ᵣ, with a corresponding increase in the number of release sites, which increased spike fidelity during high activity. Neither quantal size nor average excitatory postsynaptic current changed. After returning to control conditions, P ᵣ recovered to high. These changes seem to reflect a homeostatic response to enhance fidelity. Information processing in the brain requires reliable synaptic transmission. High reliability at specialized auditory nerve synapses in the cochlear nucleus results from many release sites ( N ), high probability of neurotransmitter release ( P ᵣ), and large quantal size ( Q ). However, high P ᵣ also causes auditory nerve synapses to depress strongly when activated at normal rates for a prolonged period, which reduces fidelity. We studied how synapses are influenced by prolonged activity by exposing mice to constant, nondamaging noise and found that auditory nerve synapses changed to facilitating, reflecting low P ᵣ. For mice returned to quiet, synapses recovered to normal depression, suggesting that these changes are a homeostatic response to activity. Two additional properties, Q and average excitatory postsynaptic current (EPSC) amplitude, were unaffected by noise rearing, suggesting that the number of release sites ( N ) must increase to compensate for decreased P ᵣ. These changes in N and P ᵣ were confirmed physiologically using the integration method. Furthermore, consistent with increased N , endbulbs in noise-reared animals had larger VGlut1-positive puncta, larger profiles in electron micrographs, and more release sites per profile. In current-clamp recordings, noise-reared BCs had greater spike fidelity even during high rates of synaptic activity. Thus, auditory nerve synapses regulate excitability through an activity-dependent, homeostatic mechanism, which could have major effects on all downstream processing. Our results also suggest that noise-exposed bushy cells would remain hyperexcitable for a period after returning to normal quiet conditions, which could have perceptual consequences.

Besides controlling a wide variety of cell functions, T-type channels have been shown to regulate neurotransmitter release in peripheral and central synapses and neuroendocrine cells. Growing evidence over the last 10 years suggests a key role of Cav3.2 and Cav3.1 channels in controlling basal neurosecretion near resting conditions and sustained release during mild stimulations. In some cases, the contribution of low-voltage-activated (LVA) channels is not directly evident but requires either the activation of coupled presynaptic receptors, block of ion channels, or chelation of metal ions. Concerning the coupling to the secretory machinery, T-type channels appear loosely coupled to neurotransmitter and hormone release. In neurons, Cav3.2 and Cav3.1 channels mainly control the asynchronous appearance of “minis” [miniature inhibitory postsynaptic currents (mIPSCs) and miniature excitatory postsynaptic currents (mEPSCs)]. The same loose coupling is evident from membrane capacity and amperometric recordings in chromaffin cells and melanotropes where the low-threshold-driven exocytosis possesses the same linear Ca 2+ dependence of the other voltage-gated Ca 2+ channels (Cav1 and Cav2) that is strongly attenuated by slow calcium buffers. The intriguing issue is that, despite not expressing a consensus “synprint” site, Cav3.2 channels do interact with syntaxin 1A and SNAP-25 and, thus, may form nanodomains with secretory vesicles that can be regulated at low voltages. In this review, we discuss all the past and recent issues related to T-type channel-secretion coupling in neurons and neuroendocrine cells.

At the first synapse in the auditory pathway, the receptor potential of mechanosensory hair cells is converted into a firing pattern in auditory nerve fibers. For the accurate coding of timing and intensity of sound signals, transmitter release at this synapse must occur with the highest precision. To measure directly the transfer characteristics of the hair cell afferent synapse, we implemented simultaneous whole-cell recordings from mammalian inner hair cells (IHCs) and auditory nerve fiber terminals that typically receive input from a single ribbon synapse. During a 1-s IHC depolarization, the synaptic response depressed >90%, representing the main source for adaptation in the auditory nerve. Synaptic depression was slightly affected by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor desensitization; however, it was mostly caused by reduced vesicular release. When the transfer function between transmitter release and Ca²⁺ influx was tested at constant open probability for Ca²⁺ channels (potentials >0 mV), a super linear relation was found. This relation is presumed to result from the cooperative binding of three to four Ca²⁺ ions at the Ca²⁺ sensor. However, in the physiological range for receptor potentials (-50 to -30 mV), the relation between Ca²⁺ influx and afferent activity was linear, assuring minimal distortion in the coding of sound intensity. Changes in Ca²⁺ influx caused an increase in release probability, but not in the average size of multivesicular synaptic events. By varying Ca²⁺ buffering in the IHC, we further investigate how Ca²⁺ channel and Ca²⁺ sensor at this synapse might relate.

Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway for the central control of reproduction. The coordinated and timely activation of these hypothalamic neurons, which determines sexual development and adult reproductive function, lies under the tight control of a complex array of excitatory and inhibitory transsynaptic inputs. In addition, research conducted over the past 20 years has unveiled the major contribution of glial cells to the control of GnRH neurons. Glia use a variety of molecular and cellular strategies to modulate GnRH neuronal function both at the level of their cell bodies and at their nerve terminals. These mechanisms include the secretion of bioactive molecules that exert paracrine effects on GnRH neurons, juxtacrine interactions between glial cells and GnRH neurons via adhesive molecules and the morphological plasticity of the glial coverage of GnRH neurons. It now appears that glial cells are integral components, along with upstream neuronal networks, of the central control of GnRH neuronal function. This review attempts to summarize our current knowledge of the mechanisms used by glial cells to control GnRH neuronal activity and secretion.

Information in neurons flows from synapses, through the dendrites and cell body (soma), and, finally, along the axon as spikes of electrical activity that will ultimately release neurotransmitters from the nerve terminals. However, the dendrites of many neurons also have a secretory role, transmitting information back to afferent nerve terminals. In some central nervous system neurons, spikes that originate at the soma can travel along dendrites as well as axons, and may thus elicit secretion from both compartments. Here, we show that in hypothalamic oxytocin neurons, agents that mobilize intracellular Ca(2+) induce oxytocin release from dendrites without increasing the electrical activity of the cell body, and without inducing secretion from the nerve terminals. Conversely, electrical activity in the cell bodies can cause the secretion of oxytocin from nerve terminals with little or no release from the dendrites. Finally, mobilization of intracellular Ca(2+) can also prime the releasable pool of oxytocin in the dendrites. This priming action makes dendritic oxytocin available for release in response to subsequent spike activity. Priming persists for a prolonged period, changing the nature of interactions between oxytocin neurons and their neighbours.