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ACS Chemical Neuroscience Jan 2015A great deal of research has focused on investigating neurobiological alterations induced by chronic psychostimulant use in an effort to describe, understand, and treat... (Review)
Review
A great deal of research has focused on investigating neurobiological alterations induced by chronic psychostimulant use in an effort to describe, understand, and treat the pathology of psychostimulant addiction. It has been known for several decades that dopamine neurotransmission in the nucleus accumbens is integrally involved in the selection and execution of motivated and goal-directed behaviors, and that psychostimulants act on this system to exert many of their effects. As such, a large body of work has focused on defining the consequences of psychostimulant use on dopamine signaling in the striatum as it relates to addictive behaviors. Here, we review presynaptic dopamine terminal alterations observed following self-administration of cocaine and amphetamine, as well as possible mechanisms by which these alterations occur and their impact on the progression of addiction.
Topics: Adaptation, Biological; Animals; Central Nervous System Stimulants; Dopamine; Humans; Presynaptic Terminals; Self Administration
PubMed: 25491345
DOI: 10.1021/cn5002705 -
The Neuroscientist : a Review Journal... Aug 2019Deposition of amyloid plaques in limbic and associative cortices is amongst the most recognized histopathologic hallmarks of Alzheimer's disease. Despite decades of... (Review)
Review
Deposition of amyloid plaques in limbic and associative cortices is amongst the most recognized histopathologic hallmarks of Alzheimer's disease. Despite decades of research, there is a lack of consensus over the impact of plaques on neuronal function, with their role in cognitive decline and memory loss undecided. Evidence has emerged suggesting complex and localized axonal pathology around amyloid plaques, with a significant fraction of swellings and dystrophies becoming enriched with putative synaptic vesicles and presynaptic proteins normally colocalized at hotspots of transmitter release. In the absence of hallmark active zone proteins and postsynaptic receptive elements, the axonal swellings surrounding amyloid plaques have been suggested as sites for ectopic release of glutamate, which under reduced clearance can lead to elevated local excitatory drive. Throughout this review, we consider the emerging data suggestive of amyloid plaques as hotspots of compulsive glutamatergic activity. Evidence for local and long-range effects of nonsynaptic glutamate is discussed in the context of circuit dysfunctions and neurodegenerative changes of Alzheimer's disease.
Topics: Alzheimer Disease; Animals; Axons; Brain; Glutamic Acid; Humans; Plaque, Amyloid; Presynaptic Terminals
PubMed: 30051750
DOI: 10.1177/1073858418791128 -
The Journal of Cell Biology Jul 2017Synapses are functionally distinct neuronal compartments that are critical for brain function, with synaptic dysfunction being an early pathological feature in aging and... (Review)
Review
Synapses are functionally distinct neuronal compartments that are critical for brain function, with synaptic dysfunction being an early pathological feature in aging and disease. Given the large number of proteins needed for synaptic function, the proliferation of defective proteins and the subsequent loss of protein homeostasis may be a leading cause of synaptic dysfunction. Autophagic mechanisms are cellular digestion processes that recycle cellular components and contribute to protein homeostasis. Autophagy is important within the nervous system, but its function in specific compartments such as the synapse has been unclear. Evidence from research on both autophagy and synaptic function suggests that there are links between the two and that synaptic homeostasis during aging requires autophagy to regulate protein homeostasis. Exciting new work on autophagy-modulating proteins that are enriched at the synapse has begun to link autophagy to synapses and synaptic dysfunction in disease. A better understanding of these links will help us harness the potential therapeutic benefits of autophagy in combating age-related disorders of the nervous system.
Topics: Animals; Autophagy; Brain; Homeostasis; Humans; Nerve Tissue Proteins; Neurons; Presynaptic Terminals; Signal Transduction; Synaptic Potentials; Synaptic Transmission
PubMed: 28515275
DOI: 10.1083/jcb.201611113 -
Neuron Feb 2015The function of the nervous system depends on the exocytotic release of neurotransmitter from synaptic vesicles (SVs). To sustain neurotransmission, SV membranes need to... (Review)
Review
The function of the nervous system depends on the exocytotic release of neurotransmitter from synaptic vesicles (SVs). To sustain neurotransmission, SV membranes need to be retrieved, and SVs have to be reformed locally within presynaptic nerve terminals. In spite of more than 40 years of research, the mechanisms underlying presynaptic membrane retrieval and SV recycling remain controversial. Here, we review the current state of knowledge in the field, focusing on the molecular mechanism involved in presynaptic membrane retrieval and SV reformation. We discuss the challenges associated with studying these pathways and present perspectives for future research.
Topics: Animals; Endocytosis; Exocytosis; Humans; Presynaptic Terminals; Synaptic Membranes; Synaptic Vesicles
PubMed: 25654254
DOI: 10.1016/j.neuron.2014.12.016 -
Journal of Neurophysiology Jul 2016Presynaptic inhibition is a very powerful inhibitory mechanism and, despite many detailed studies, its purpose is still only partially understood. One accepted function... (Review)
Review
Presynaptic inhibition is a very powerful inhibitory mechanism and, despite many detailed studies, its purpose is still only partially understood. One accepted function is that, by reducing afferent inflow to the spinal cord and brainstem, the tonic level of presynaptic inhibition prevents sensory systems from being overloaded. A corollary of this function is that much of the incoming sensory data from peripheral receptors must be redundant, and this conclusion is reinforced by observations on patients with sensory neuropathies or congenital obstetric palsy in whom normal sensation may be preserved despite loss of sensory fibers. The modulation of incoming signals by presynaptic inhibition has a further function in operating a "gate" in the dorsal horn, thereby determining whether peripheral stimuli are likely to be perceived as painful. On the motor side, the finding that even minimal voluntary movement of a single toe is associated with widespread inhibition in the lumbosacral cord points to another function for presynaptic inhibition: to prevent reflex perturbations from interfering with motor commands. This last function, together with the normal suppression of muscle and cutaneous reflex activity at rest, is consistent with Hughlings Jackson's concept of evolving neural hierarchies, with each level inhibiting the one below it.
Topics: Animals; England; History, 19th Century; Humans; Models, Neurological; Neural Inhibition; Neurosciences; Presynaptic Terminals
PubMed: 27121579
DOI: 10.1152/jn.00371.2015 -
The Journal of Neuroscience : the... Mar 2022Efficient and reliable neurotransmission requires precise coupling between action potentials (APs), Ca entry and neurotransmitter release. However, Ca requirements for...
Efficient and reliable neurotransmission requires precise coupling between action potentials (APs), Ca entry and neurotransmitter release. However, Ca requirements for release, including the number of channels required, their subtypes, and their location with respect to primed vesicles, remains to be precisely defined for central synapses. Indeed, Ca entry may occur through small numbers or even single open Ca channels, but these questions remain largely unexplored in simple active zone (AZ) synapses common in the nervous system, and key to addressing Ca channel and synaptic dysfunction underlying numerous neurologic and neuropsychiatric disorders. Here, we present single channel analysis of evoked AZ Ca entry, using cell-attached patch clamp and lattice light-sheet microscopy (LLSM), resolving small channel numbers evoking Ca entry following depolarization, at single AZs in individual central lamprey reticulospinal presynaptic terminals from male and females. We show a small pool (mean of 23) of Ca channels at each terminal, comprising N-(CaV2.2), P/Q-(CaV2.1), and R-(CaV2.3) subtypes, available to gate neurotransmitter release. Significantly, of this pool only one to seven channels (mean of 4) open on depolarization. High temporal fidelity lattice light-sheet imaging reveals AP-evoked Ca transients exhibiting quantal amplitude variations of 0-6 event sizes between individual APs and stochastic variation of precise locations of Ca entry within the AZ. Further, total Ca channel numbers at each AZ correlate to the number of presynaptic primed synaptic vesicles. Dispersion of channel openings across the AZ and the similar number of primed vesicles and channels indicate that Ca entry via as few as one channel may trigger neurotransmitter release. Presynaptic Ca entry through voltage-gated calcium channels (VGCCs) causes neurotransmitter release. To understand neurotransmission, its modulation, and plasticity, we must quantify Ca entry and its relationship to vesicle fusion. This requires direct recordings from active zones (AZs), previously possible only at calyceal terminals containing many AZs, where few channels open following action potentials (APs; Sheng et al., 2012), and even single channel openings may trigger release (Stanley, 1991, 1993). However, recording from more conventional terminals with single AZs commonly found centrally has thus far been impossible. We addressed this by cell-attached recordings from acutely dissociated single lamprey giant axon AZs, and by lattice light sheet microscopy of presynaptic Ca entry. We demonstrate nanodomains of presynaptic VGCCs coupling with primed vesicles with 1:1 stoichiometry.
Topics: Animals; Calcium; Female; Lampreys; Male; Neurotransmitter Agents; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 35063999
DOI: 10.1523/JNEUROSCI.2207-21.2022 -
Pharmacological Reviews Apr 2017Presynaptic nerve terminals are highly specialized vesicle-trafficking machines. Neurotransmitter release from these terminals is sustained by constant local recycling... (Review)
Review
Presynaptic nerve terminals are highly specialized vesicle-trafficking machines. Neurotransmitter release from these terminals is sustained by constant local recycling of synaptic vesicles independent from the neuronal cell body. This independence places significant constraints on maintenance of synaptic protein complexes and scaffolds. Key events during the synaptic vesicle cycle-such as exocytosis and endocytosis-require formation and disassembly of protein complexes. This extremely dynamic environment poses unique challenges for proteostasis at synaptic terminals. Therefore, it is not surprising that subtle alterations in synaptic vesicle cycle-associated proteins directly or indirectly contribute to pathophysiology seen in several neurologic and psychiatric diseases. In contrast to the increasing number of examples in which presynaptic dysfunction causes neurologic symptoms or cognitive deficits associated with multiple brain disorders, synaptic vesicle-recycling machinery remains an underexplored drug target. In addition, irrespective of the involvement of presynaptic function in the disease process, presynaptic machinery may also prove to be a viable therapeutic target because subtle alterations in the neurotransmitter release may counter disease mechanisms, correct, or compensate for synaptic communication deficits without the need to interfere with postsynaptic receptor signaling. In this article, we will overview critical properties of presynaptic release machinery to help elucidate novel presynaptic avenues for the development of therapeutic strategies against neurologic and neuropsychiatric disorders.
Topics: Animals; Endocytosis; Exocytosis; Humans; Presynaptic Terminals; Synaptic Vesicles
PubMed: 28265000
DOI: 10.1124/pr.116.013342 -
The Journal of Physiology Dec 2003Exocytosis of neurotransmitter from a synaptic vesicle is followed by efficient retrieval of its constituent membrane and proteins. Real-time measurements indicate that... (Review)
Review
Exocytosis of neurotransmitter from a synaptic vesicle is followed by efficient retrieval of its constituent membrane and proteins. Real-time measurements indicate that fast and slow modes of retrieval operate in parallel at a number of presynaptic terminals. Two mechanisms can be distinguished by electron microscopy: clathrin-mediated retrieval of small vesicles and bulk retrieval of large cisternae. Methods that investigate the behaviour of individual vesicles have recently demonstrated a third route of retrieval: the rapid reversal of a pore-like connection between the vesicle and surface ('kiss-and-run'). Key aims for the future are to identify the molecules underlying different mechanisms of endocytosis at the synapse and the signals that select between them.
Topics: Animals; Clathrin; Dynamins; Endocytosis; Hippocampus; Kinetics; Microscopy, Electron; Models, Neurological; Neuromuscular Junction; Presynaptic Terminals; Synapses
PubMed: 12963793
DOI: 10.1113/jphysiol.2003.049221 -
Neuron Sep 2008Voltage-gated calcium (Ca(2+)) channels initiate release of neurotransmitters at synapses, and regulation of presynaptic Ca(2+) channels has a powerful influence on... (Review)
Review
Voltage-gated calcium (Ca(2+)) channels initiate release of neurotransmitters at synapses, and regulation of presynaptic Ca(2+) channels has a powerful influence on synaptic strength. Presynaptic Ca(2+) channels form a large signaling complex, which targets synaptic vesicles to Ca(2+) channels for efficient release and mediates Ca(2+) channel regulation. Presynaptic plasticity regulates synaptic function on the timescale of milliseconds to minutes in response to neurotransmitters and the frequency of action potentials. This article reviews the regulation of presynaptic Ca(2+) channels by effectors and regulators of Ca(2+) signaling and describes the emerging evidence for a critical role of Ca(2+) channel regulation in control of neurotransmission and in presynaptic plasticity. Failure of function and regulation of presynaptic Ca(2+) channels leads to migraine, ataxia, and potentially other forms of neurological disease. We propose that presynaptic Ca(2+) channels serve as the regulatory node in a dynamic, multilayered signaling network that exerts short-term control of neurotransmission in response to synaptic activity.
Topics: Animals; Calcium Channels; Calcium Signaling; Exocytosis; Humans; Neuronal Plasticity; Neurotransmitter Agents; Presynaptic Terminals; SNARE Proteins; Second Messenger Systems; Synaptic Transmission; Synaptic Vesicles
PubMed: 18817729
DOI: 10.1016/j.neuron.2008.09.005 -
International Journal of Molecular... Jul 2019Synaptosomes are used to decipher the mechanisms involved in chemical transmission, since they permit highlighting the mechanisms of transmitter release and confirming... (Review)
Review
Synaptosomes are used to decipher the mechanisms involved in chemical transmission, since they permit highlighting the mechanisms of transmitter release and confirming whether the activation of presynaptic receptors/enzymes can modulate this event. In the last two decades, important progress in the field came from the observations that synaptosomes retain changes elicited by both "in vivo" and "in vitro" chemical stimulation. The novelty of these studies is the finding that these adaptations persist beyond the washout of the triggering drug, emerging subsequently as functional modifications of synaptosomal performances, including release efficiency. These findings support the conclusion that synaptosomes are plastic entities that respond dynamically to ambient stimulation, but also that they "learn and memorize" the functional adaptation triggered by exposure to chemical agents. This work aims at reviewing the results so far available concerning this form of synaptosomal learning, also highlighting the role of these chemical adaptations in pathological conditions.
Topics: Adaptation, Physiological; Animals; Disease Susceptibility; Glutamic Acid; Humans; Learning; Memory; Neurotransmitter Agents; Presynaptic Terminals; Receptors, Cell Surface; Synaptosomes
PubMed: 31349638
DOI: 10.3390/ijms20153641