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The most prevalent form of dementia in the elderly is Alzheimer's disease. A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42 (Aβ42), a small hydrophobic peptide. Unfortunately, attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease. It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach. The accumulation of Aβ42 seems to affect various aspects of physiological cell functions. In this review, we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction, with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release. We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer's disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease. Although the precise mechanisms that trigger synaptic dysfunction are still under investigation, the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention.

The central nervous system contains several modalities for neurotransmitter release: phasic (synchronous), asynchronous, and multivesicular. This review summarizes results from studies in recent years demonstrating the involvement of different calcium sensors in triggering synchronous and asynchronous neurotransmitter release. In addition, the possible sources of presynaptic Ca2+ triggering asynchronous neurotransmitter release are considered, along with the possible mechanisms of multivesicular neurotransmitter release.

There is an error in the grant number in the Financial Disclosure (FD) statement for this article. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 1.

Homeostatic plasticity is a process by which neurons adapt to the overall network activity to keep their firing rates in a reasonable range. At the cellular level this kind of plasticity comprises modulation of cellular excitability and tuning of synaptic strength. In this review we concentrate on presynaptic homeostatic plasticity controlling the efficacy of neurotransmitter release from presynaptic boutons. While morphological and electrophysiological approaches were successful to describe homeostatic plasticity-induced changes in the presynaptic architecture and function, cellular and molecular mechanisms underlying those modifications remained largely unknown for a long time. We summarize the latest progress made in the understanding of homeostasis-induced regulation of different steps of the synaptic vesicle cycle and the molecular machineries involved in this process. We particularly focus on the role of presynaptic scaffolding proteins, which functionally and spatially organize synaptic vesicle clusters, neurotransmitter release sites and the associated endocytic machinery. These proteins turned out to be major presynaptic substrates for remodeling during homeostatic plasticity. Finally, we discuss cellular processes and signaling pathways acting during homeostatic molecular remodeling and their potential involvement in the maladaptive plasticity occurring in multiple neuropathologic conditions such as neurodegeneration, epilepsy and neuropsychiatric disorders.

Membrane fusion triggered by Ca 2+ is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion and other regulated exocytic processes 1 – 4 . For neurotransmitter release, the Ca 2+ sensitivity is introduced by interactions between the Ca 2+ sensor synaptotagmin and the SNARE complex 5 , and sequence conservation and functional studies suggest that this mechanism is also conserved for mucin secretion 6 . Disruption of Ca 2+ -triggered membrane fusion by a pharmacological agent would have therapeutic value for mucus hypersecretion as it is the major cause of airway obstruction in the pathophysiology of respiratory viral infection, asthma, chronic obstructive pulmonary disease and cystic fibrosis 7 – 11 . Here we designed a hydrocarbon-stapled peptide that specifically disrupts Ca 2+ -triggered membrane fusion by interfering with the so-called primary interface between the neuronal SNARE complex and the Ca 2+ -binding C2B domain of synaptotagmin-1. In reconstituted systems with these neuronal synaptic proteins or with their airway homologues syntaxin-3, SNAP-23, VAMP8, synaptotagmin-2, along with Munc13-2 and Munc18-2, the stapled peptide strongly suppressed Ca 2+ -triggered fusion at physiological Ca 2+ concentrations. Conjugation of cell-penetrating peptides to the stapled peptide resulted in efficient delivery into cultured human airway epithelial cells and mouse airway epithelium, where it markedly and specifically reduced stimulated mucin secretion in both systems, and substantially attenuated mucus occlusion of mouse airways. Taken together, peptides that disrupt Ca 2+ -triggered membrane fusion may enable the therapeutic modulation of mucin secretory pathways. Peptides that disrupt Ca 2+ -triggered membrane fusion may enable the therapeutic modulation of mucin secretory pathways.

Key Points The fundamental variables of small-molecule–neuropeptide co-transmission, including the potential degrees of freedom at particular presynaptic and postsynaptic profiles, and the impact of presynaptic neuron firing rate, modulatory state and extracellular peptidase activity, act to increase the complexity of synaptic transmission. There is considerable diversity in the consequences for synaptic transmission resulting from small-molecule–neuropeptide co-transmission at identified synapses, and their impact on behaviour. One highlight is that the various mechanisms by which this co-transmission influences synapses (for example, convergent or divergent co-transmission, firing rate-dependent co-transmitter release, and so on) are shared across invertebrate and vertebrate species. Using exogenously applied neuropeptides has provided many insights into their modulatory actions, but this approach also has limitations and can lead to erroneous conclusions, as illustrated by studies in the crustacean stomatogastric ganglion that compare the influence of exogenous versus neuronally released neuropeptides from identified neurons. Extending small-molecule–neuropeptide co-transmission studies from individual synapses to their impact on microcircuits, results from the crustacean stomatogastric system are presented to elucidate the impact of convergent versus divergent co-transmission, to separate regulation of co-transmitters and to show the distinct influence on the same microcircuits of different neurons with shared co-transmitters. Work from the stomatogastric system is also used to provide insight regarding the imperfect match between the influence of apparently equivalent, small-molecule–neuropeptide co-transmitting neurons on the same microcircuits in different species. Small-molecule–neuropeptide co-transmission is pervasive throughout the nervous system of all animals. In this Review, Nusbaum, Blitz and Marder discuss how co-transmission is an important source for the considerable flexibility that has been established for synapses, circuits and behaviour. Colocalization of small-molecule and neuropeptide transmitters is common throughout the nervous system of all animals. The resulting co-transmission, which provides conjoint ionotropic ('classical') and metabotropic ('modulatory') actions, includes neuropeptide- specific aspects that are qualitatively different from those that result from metabotropic actions of small-molecule transmitter release. Here, we focus on the flexibility afforded to microcircuits by such co-transmission, using examples from various nervous systems. Insights from such studies indicate that co-transmission mediated even by a single neuron can configure microcircuit activity via an array of contributing mechanisms, operating on multiple timescales, to enhance both behavioural flexibility and robustness.

The human olfactory system comprises olfactory receptor neurons, projection neurons, and interneurons that perform remarkably sophisticated functions, including sensing, filtration, memorization, and forgetting of chemical stimuli for perception. Developing an artificial olfactory system that can mimic these functions has proved to be challenging. Herein, inspired by the neuronal network inside the glomerulus of the olfactory bulb, we present an artificial chemosensory neuronal synapse that can sense chemical stimuli and mimic the functions of excitatory and inhibitory neurotransmitter release in the synapses between olfactory receptor neurons, projection neurons, and interneurons. The proposed device is based on a flexible organic electrochemical transistor gated by the potential generated by the interaction of gas molecules with ions in a chemoreceptive ionogel. The combined use of a chemoreceptive ionogel and an organic semiconductor channel allows for a long retentive memory in response to chemical stimuli. Long-term memorization of the excitatory chemical stimulus can be also erased by applying an inhibitory electrical stimulus due to ion dynamics in the chemoresponsive ionogel gate electrolyte. Applying a simple device design, we were able to mimic the excitatory and inhibitory synaptic functions of chemical synapses in the olfactory system, which can further advance the development of artificial neuronal systems for biomimetic chemosensory applications. Developing an artificial olfactory system that can mimic the biological functions remains a challenge. Here, the authors develop an artificial chemosensory synapse based on a flexible organic electrochemical transistor gated by the potential generated by the interaction of gas molecules with ions in a chemoreceptive ionogel.

Persistent neural activity in cortical, hippocampal, and motor networks has been described as mediating working memory for transiently encountered stimuli 1 , 2 . Internal emotional states, such as fear, also persist following exposure to an inciting stimulus 3 , but it is unclear whether slow neural dynamics are involved in this process. Neurons in the dorsomedial and central subdivisions of the ventromedial hypothalamus (VMHdm/c) that express the nuclear receptor protein NR5A1 (also known as SF1) are necessary for defensive responses to predators in mice 4 – 7 . Optogenetic activation of these neurons, referred to here as VMHdm SF1 neurons, elicits defensive behaviours that outlast stimulation 5 , 8 , which suggests the induction of a persistent internal state of fear or anxiety. Here we show that in response to naturalistic threatening stimuli, VMHdm SF1 neurons in mice exhibit activity that lasts for many tens of seconds. This persistent activity was correlated with, and required for, persistent defensive behaviour in an open-field assay, and depended on neurotransmitter release from VMHdm SF1 neurons. Stimulation and calcium imaging in acute slices showed that there is local excitatory connectivity between VMHdm SF1 neurons. Microendoscopic calcium imaging of VMHdm SF1 neurons revealed that persistent activity at the population level reflects heterogeneous dynamics among individual cells. Unexpectedly, distinct but overlapping VMHdm SF1 subpopulations were persistently activated by different modalities of threatening stimulus. Computational modelling suggests that neither recurrent excitation nor slow-acting neuromodulators alone can account for persistent activity that maintains stimulus identity. Our results show that stimulus-specific slow neural dynamics in the hypothalamus, on a time scale orders of magnitude longer than that of working memory in the cortex 9 , 10 , contribute to a persistent emotional state. Persistent neural activity in the mouse hypothalamus encodes aversive emotional states related to specific threatening stimuli.

The function of α-synuclein (α-syn) has been long debated, and two seemingly divergent views have emerged. In one, α-syn binds to VAMP2, acting as a SNARE chaperone—but with no effect on neurotransmission—while another posits that α-syn attenuates neurotransmitter release by restricting synaptic vesicle mobilization and recycling. Here, we show that α-syn–VAMP2 interactions are necessary for α-syn–induced synaptic attenuation. Our data connect divergent views and suggest a unified model of α-syn function.

Chemical synapses are heterogeneous junctions formed between neurons that are specialized for the conversion of electrical impulses into the exocytotic release of neurotransmitters. Voltage-gated Ca2+ channels play a pivotal role in this process as they are the major conduits for the Ca2+ ions that trigger the fusion of neurotransmitter-containing vesicles with the presynaptic membrane. Alterations in the intrinsic function of these channels and their positioning within the active zone can profoundly alter the timing and strength of synaptic output. Advances in optical and electron microscopic imaging, structural biology and molecular techniques have facilitated recent breakthroughs in our understanding of the properties of voltage-gated Ca2+ channels that support their presynaptic functions. Here we examine the nature of these channels, how they are trafficked to and anchored within presynaptic boutons, and the mechanisms that allow them to function optimally in shaping the flow of information through neural circuits.Voltage-gated calcium channels have an essential role in the regulation of neurotransmitter release. Dolphin and Lee describe here how advances in the techniques available to study presynaptic voltage-gated calcium channels have provided insight into their composition, trafficking, regulation and contributions to presynaptic function.