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Trends in Neurosciences Jun 2018Today, we understand peptide transmitters to be signaling molecules that modulate neural activity. However, in 1982 little was known about neuropeptides and their role... (Review)
Review
Today, we understand peptide transmitters to be signaling molecules that modulate neural activity. However, in 1982 little was known about neuropeptides and their role in neural communication. The influential 1982 paper by Jan and Jan reported definitive evidence that a presynaptically released neuropeptide evokes postsynaptic responses in an identified cholinergic synapse, thereby fueling a new era in neuroscience.
Topics: Animals; Humans; Neuropeptides; Presynaptic Terminals; Synaptic Transmission
PubMed: 29801523
DOI: 10.1016/j.tins.2018.03.013 -
Cerebral Cortex (New York, N.Y. : 1991) Aug 2018Understanding which cellular compartments are influenced during neuromodulation underpins any rational effort to explain and optimize outcomes. Axon terminals have long...
Understanding which cellular compartments are influenced during neuromodulation underpins any rational effort to explain and optimize outcomes. Axon terminals have long been speculated to be sensitive to polarization, but experimentally informed models for CNS stimulation are lacking. We conducted simultaneous intracellular recording from the neuron soma and axon terminal (blebs) during extracellular stimulation with weak sustained (DC) uniform electric fields in mouse cortical slices. Use of weak direct current stimulation (DCS) allowed isolation and quantification of changes in axon terminal biophysics, relevant to both suprathreshold (e.g., deep brain stimulation, spinal cord stimulation, and transcranial magnetic stimulation) and subthreshold (e.g., transcranial DCS and transcranial alternating current stimulation) neuromodulation approaches. Axon terminals polarized with sensitivity (mV of membrane polarization per V/m electric field) 4 times than somas. Even weak polarization (<2 mV) of axon terminals significantly changes action potential dynamics (including amplitude, duration, conduction velocity) in response to an intracellular pulse. Regarding a cellular theory of neuromodulation, we explain how suprathreshold CNS stimulation activates the action potential at terminals while subthreshold approaches modulate synaptic efficacy through axon terminal polarization. We demonstrate that by virtue of axon polarization and resulting changes in action potential dynamics, neuromodulation can influence analog-digital information processing.
Topics: Age Factors; Animals; Biophysics; Cell Polarity; Cerebral Cortex; Electric Stimulation; Evoked Potentials; Female; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Models, Neurological; Neurons; Patch-Clamp Techniques; Presynaptic Terminals
PubMed: 28655149
DOI: 10.1093/cercor/bhx158 -
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 -
Nature Reviews. Neuroscience Apr 2020Chemical synapses are heterogeneous junctions formed between neurons that are specialized for the conversion of electrical impulses into the exocytotic release of... (Review)
Review
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 Ca channels play a pivotal role in this process as they are the major conduits for the Ca 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 Ca 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.
Topics: Animals; Calcium Channels; Humans; Presynaptic Terminals; Protein Transport; Synaptic Transmission; Synaptic Vesicles
PubMed: 32161339
DOI: 10.1038/s41583-020-0278-2 -
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 -
ENeuro 2022Voltage-gated calcium channel Ca2.1 undergoes Ca-dependent facilitation and inactivation, which are important in short-term synaptic plasticity. In presynaptic...
Voltage-gated calcium channel Ca2.1 undergoes Ca-dependent facilitation and inactivation, which are important in short-term synaptic plasticity. In presynaptic terminals, Ca2.1 forms large protein complexes that include synaptotagmins. Synaptotagmin-7 (Syt-7) is essential to mediate short-term synaptic plasticity in many synapses. Here, based on evidence that Ca2.1 and Syt-7 are both required for short-term synaptic facilitation, we investigated the direct interaction of Syt-7 with Ca2.1 and probed its regulation of Ca2.1 function. We found that Syt-7 binds specifically to the α subunit of Ca2.1 through interaction with the synaptic-protein interaction (synprint) site. Surprisingly, this interaction enhances facilitation in paired-pulse protocols and accelerates the onset of facilitation. Syt-7α induces a depolarizing shift in the voltage dependence of activation of Ca2.1 and slows Ca-dependent inactivation, whereas Syt-7β and Syt-7γ have smaller effects. Our results identify an unexpected, isoform-specific interaction between Ca2.1 and Syt-7 through the synprint site, which enhances Ca2.1 facilitation and modulates its inactivation.
Topics: Calcium; Calcium Channels, N-Type; Neuronal Plasticity; Presynaptic Terminals; Synaptic Transmission; Synaptotagmins
PubMed: 35477860
DOI: 10.1523/ENEURO.0081-22.2022 -
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 -
Neuroscience Dec 2014The gate control theory proposed that the nociceptive sensory information transmitted to the brain relies on an interplay between the inputs from nociceptive and... (Review)
Review
The gate control theory proposed that the nociceptive sensory information transmitted to the brain relies on an interplay between the inputs from nociceptive and non-nociceptive primary afferent fibers. Both inputs are normally under strong inhibitory control in the spinal cord. Under healthy conditions, presynaptic inhibition activated by non-nociceptive fibers modulates the afferent input from nociceptive fibers onto spinal cord neurons, while postsynaptic inhibition controls the excitability of dorsal horn neurons, and silences the non-nociceptive information flow to nociceptive-specific (NS) projection neurons. However, under pathological conditions, this spinal inhibition may be altered and lead to chronic pain. This review summarizes our knowledge of presynaptic inhibition in pain control, with particular focus on how its alteration after nerve or tissue injury contributes to neuropathic or inflammatory pain syndromes, respectively.
Topics: Animals; Humans; Neural Inhibition; Nociceptors; Pain; Presynaptic Terminals; Spinal Cord; Synaptic Transmission
PubMed: 25255936
DOI: 10.1016/j.neuroscience.2014.09.032 -
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