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ELife Apr 2023Control of neurotransmission efficacy is central to theories of how the brain computes and stores information. Presynaptic G-protein coupled receptors (GPCRs) are...
Control of neurotransmission efficacy is central to theories of how the brain computes and stores information. Presynaptic G-protein coupled receptors (GPCRs) are critical in this problem as they locally influence synaptic strength and can operate on a wide range of time scales. Among the mechanisms by which GPCRs impact neurotransmission is by inhibiting voltage-gated calcium (Ca) influx in the active zone. Here, using quantitative analysis of both single bouton Ca influx and exocytosis, we uncovered an unexpected non-linear relationship between the magnitude of action potential driven Ca influx and the concentration of external Ca ([Ca]). We find that this unexpected relationship is leveraged by GPCR signaling when operating at the nominal physiological set point for [Ca], 1.2 mM, to achieve complete silencing of nerve terminals. These data imply that the information throughput in neural circuits can be readily modulated in an all-or-none fashion at the single synapse level when operating at the physiological set point.
Topics: Synapses; Presynaptic Terminals; Synaptic Transmission; Action Potentials; gamma-Aminobutyric Acid; Calcium
PubMed: 37014052
DOI: 10.7554/eLife.83530 -
The Journal of Physiology Dec 2017GABA receptors have been described in the axonal compartment of neurons; contrary to dendritic GABA receptors, axonal GABA receptors usually induce depolarizing...
KEY POINTS
GABA receptors have been described in the axonal compartment of neurons; contrary to dendritic GABA receptors, axonal GABA receptors usually induce depolarizing responses. In this study we describe the presence of functional axonal GABA receptors in cerebellar Purkinje cells by using a combination of direct patch-clamp recordings from the axon terminals and laser GABA photolysis. In Purkinje cells, axonal GABA receptors are depolarizing and induce an increase in neurotransmitter release that results in a change of short-term synaptic plasticity. These results contribute to our understanding of the cellular mechanisms of action of axonal GABA receptors and highlight the importance of the presynaptic compartment in neuronal computation.
ABSTRACT
In neurons of the adult brain, somatodendritic GABA receptors (GABA Rs) mediate fast synaptic inhibition and play a crucial role in synaptic integration. GABA Rs are not only present in the somatodendritic compartment, but also in the axonal compartment where they modulate action potential (AP) propagation and transmitter release. Although presynaptic GABA Rs have been reported in various brain regions, their mechanisms of action and physiological roles remain obscure, particularly at GABAergic boutons. Here, using a combination of direct whole-bouton or perforated patch-clamp recordings and local GABA photolysis in single axonal varicosities of cerebellar Purkinje cells, we investigate the subcellular localization and functional role of axonal GABA Rs both in primary cultures and acute slices. Our results indicate that presynaptic terminals of PCs carry GABA Rs that behave as auto-receptors; their activation leads to a depolarization of the terminal membrane after an AP due to the relatively high cytoplasmic Cl concentration in the axon, but they do not modulate the AP itself. Paired recordings from different terminals of the same axon show that the GABA R-mediated local depolarizations propagate substantially to neighbouring varicosities. Finally, the depolarization mediated by presynaptic GABA R activation augmented Ca influx and transmitter release, resulting in a marked effect on short-term plasticity. Altogether, our results reveal a mechanism by which presynaptic GABA Rs influence neuronal computation.
Topics: Action Potentials; Animals; Cells, Cultured; Exocytosis; Female; Male; Presynaptic Terminals; Purkinje Cells; Rats; Rats, Wistar; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 29072780
DOI: 10.1113/JP275369 -
The Neuroscientist : a Review Journal... Jun 2012Synapses represent the main junctures of communication between neurons in the nervous system. In many neurotransmitter systems, a fraction of presynaptic terminals fails... (Review)
Review
Synapses represent the main junctures of communication between neurons in the nervous system. In many neurotransmitter systems, a fraction of presynaptic terminals fails to release vesicles in response to action potential stimulation and strong calcium influx. These silent presynaptic terminals exhibit a reversible functional dormancy beyond low vesicle release probability, and dormancy status may have important implications in neural function. Recent advances have implicated presynaptic proteins interacting with vesicles downstream of cAMP and protein kinase A signaling cascades in modulating the number of these mute presynaptic terminals, and dormancy induction may represent a homeostatic neuroprotective mechanism active during pathological insults involving excitotoxicity. Interestingly, dormancy reversal may also be induced during Hebbian plasticity. Here, details of synaptic dormancy, recent insights into the molecular signaling cascades involved, and potential clinical and mechanistic implications of this form of synaptic plasticity are described.
Topics: Animals; Humans; Neuronal Plasticity; Presynaptic Terminals; Signal Transduction; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 21908849
DOI: 10.1177/1073858411418525 -
Neuron Mar 2021Tau is a major driver of neurodegeneration and is implicated in over 20 diseases. Tauopathies are characterized by synaptic loss and neuroinflammation, but it is unclear...
Tau is a major driver of neurodegeneration and is implicated in over 20 diseases. Tauopathies are characterized by synaptic loss and neuroinflammation, but it is unclear if these pathological events are causally linked. Tau binds to Synaptogyrin-3 on synaptic vesicles. Here, we interfered with this function to determine the role of pathogenic Tau at pre-synaptic terminals. We show that heterozygous knockout of synaptogyrin-3 is benign in mice but strongly rescues mutant Tau-induced defects in long-term synaptic plasticity and working memory. It also significantly rescues the pre- and post-synaptic loss caused by mutant Tau. However, Tau-induced neuroinflammation remains clearly upregulated when we remove the expression of one allele of synaptogyrin-3. Hence neuroinflammation is not sufficient to cause synaptic loss, and these processes are separately induced in response to mutant Tau. In addition, the pre-synaptic defects caused by mutant Tau are enough to drive defects in cognitive tasks.
Topics: Animals; Encephalitis; Female; Hippocampus; Male; Memory Disorders; Mice, Knockout; Microglia; Neuronal Plasticity; Presynaptic Terminals; Synaptogyrins; tau Proteins; Mice
PubMed: 33472038
DOI: 10.1016/j.neuron.2020.12.016 -
Cells Mar 2021In presynaptic terminals, synaptic vesicles (SVs) are found in a discrete cluster that includes a reserve pool that is mobilized during synaptic activity. Synapsins... (Review)
Review
In presynaptic terminals, synaptic vesicles (SVs) are found in a discrete cluster that includes a reserve pool that is mobilized during synaptic activity. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. Here, we summarize what is known about the role of synapsins in clustering of SVs and evaluate experimental evidence supporting these two models.
Topics: Animals; Exocytosis; Humans; Models, Neurological; Presynaptic Terminals; Protein Binding; Protein Transport; Synapsins; Synaptic Transmission; Synaptic Vesicles
PubMed: 33809712
DOI: 10.3390/cells10030658 -
Neuromolecular Medicine Sep 2015Neurons and especially their synapses often project long thin processes that can invaginate neighboring neuronal or glial cells. These "invaginating projections" can... (Review)
Review
Neurons and especially their synapses often project long thin processes that can invaginate neighboring neuronal or glial cells. These "invaginating projections" can occur in almost any combination of postsynaptic, presynaptic, and glial processes. Invaginating projections provide a precise mechanism for one neuron to communicate or exchange material exclusively at a highly localized site on another neuron, e.g., to regulate synaptic plasticity. The best-known types are postsynaptic projections called "spinules" that invaginate into presynaptic terminals. Spinules seem to be most prevalent at large very active synapses. Here, we present a comprehensive review of all kinds of invaginating projections associated with both neurons in general and more specifically with synapses; we describe them in all animals including simple, basal metazoans. These structures may have evolved into more elaborate structures in some higher animal groups exhibiting greater synaptic plasticity. In addition to classic spinules and filopodial invaginations, we describe a variety of lesser-known structures such as amphid microvilli, spinules in giant mossy terminals and en marron/brush synapses, the highly specialized fish retinal spinules, the trophospongium, capitate projections, and fly gnarls, as well as examples in which the entire presynaptic or postsynaptic process is invaginated. These various invaginating projections have evolved to modify the function of a particular synapse, or to channel an effect to one specific synapse or neuron, without affecting those nearby. We discuss how they function in membrane recycling, nourishment, and cell signaling and explore how they might change in aging and disease.
Topics: Animals; Biological Evolution; Cell Surface Extensions; Humans; Invertebrates; Neuronal Plasticity; Neurons; Paracrine Communication; Post-Synaptic Density; Presynaptic Terminals; Pseudopodia; Species Specificity; Synapses; Vertebrates
PubMed: 26007200
DOI: 10.1007/s12017-015-8358-6 -
The Journal of Physiology Feb 2016Synaptic communication between neurons is a highly dynamic process involving specialized structures. At the level of the presynaptic terminal, neurotransmission is... (Review)
Review
Synaptic communication between neurons is a highly dynamic process involving specialized structures. At the level of the presynaptic terminal, neurotransmission is ensured by fusion of vesicles to the membrane, which releases neurotransmitter in the synaptic cleft. Depending on the level of activity experienced by the terminal, the spatiotemporal properties of calcium invasion will dictate the timing and the number of vesicles that need to be released. Diverse presynaptic firing patterns are translated to neurotransmitter release with a distinct temporal feature. Complex patterns of neurotransmitter release can be achieved when different vesicles respond to distinct calcium dynamics in the presynaptic terminal. Specific vesicles from different pools are recruited during various modes of release as the particular molecular composition of their membrane proteins define their functional properties. Such diversity endows the presynaptic terminal with the ability to respond to distinct physiological signals via the mobilization of specific subpopulation of vesicles. There are several mechanisms by which a diverse vesicle population could be generated in single presynaptic terminals, including distinct recycling pathways that utilize various adaptor proteins. Several additional factors could potentially contribute to the development of a heterogeneous vesicle pool such as specialized release sites, spatial segregation within the terminal and specialized delivery pathways. Among these factors molecular heterogeneity plays a central role in defining the functional properties of different subpopulations of vesicles.
Topics: Animals; Calcium; Exocytosis; Humans; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 26614712
DOI: 10.1113/JP270194 -
Current Opinion in Neurobiology Apr 2017Effective adaptation of neural circuit function to a changing environment requires many forms of plasticity. Among these, structural plasticity is one of the most... (Review)
Review
Effective adaptation of neural circuit function to a changing environment requires many forms of plasticity. Among these, structural plasticity is one of the most durable, and is also an intrinsic part of the developmental logic for the formation and refinement of synaptic connectivity. Structural plasticity of presynaptic sites can involve the addition, remodeling, or removal of pre- and post-synaptic elements. However, this requires coordination of morphogenesis and assembly of the subcellular machinery for neurotransmitter release within the presynaptic neuron, as well as coordination of these events with the postsynaptic cell. While much progress has been made in revealing the cell biological mechanisms of postsynaptic structural plasticity, our understanding of presynaptic mechanisms is less complete.
Topics: Animals; Drosophila; Neuronal Plasticity; Presynaptic Terminals; Synaptic Transmission
PubMed: 28388491
DOI: 10.1016/j.conb.2017.03.003 -
The Journal of Neuroscience : the... Sep 2020Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but...
Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but their relative impact on fidelity is unknown. To address this issue, we studied auditory nerve synapses onto bushy cells in the cochlear nucleus of mice of both sexes. These synapses undergo bidirectional presynaptic and postsynaptic homeostatic changes with increased and decreased acoustic stimulation. We found that both young and mature synapses exhibit similar activity-dependent changes in short-term depression. Experiments using chelators and imaging both indicated that presynaptic Ca influx decreased after noise exposure, and increased after ligating the ear canal. By contrast, Ca cooperativity was unaffected. Experiments using specific antagonists suggest that occlusion leads to changes in the Ca channel subtypes driving neurotransmitter release. Furthermore, dynamic-clamp experiments revealed that spike fidelity primarily depended on changes in presynaptic depression, with some contribution from changes in postsynaptic intrinsic properties. These experiments indicate that presynaptic Ca influx is homeostatically regulated to enhance synaptic fidelity. Homeostatic mechanisms in synapses maintain stable function in the face of different levels of activity. Both juvenile and mature auditory nerve synapses onto bushy cells modify short-term depression in different acoustic environments, which raises the question of what the underlying presynaptic mechanisms are and the relative importance of presynaptic and postsynaptic contributions to the faithful transfer of information. Changes in short-term depression under different acoustic conditions were a result of changes in presynaptic Ca influx. Spike fidelity was affected by both presynaptic and postsynaptic changes after ear occlusion and was only affected by presynaptic changes after noise-rearing. These findings are important for understanding regulation of auditory synapses under normal conditions and also in disorders following noise exposure or conductive hearing loss.
Topics: Animals; Auditory Perception; Calcium; Cochlear Nerve; Cochlear Nucleus; Female; Homeostasis; Male; Mice; Mice, Inbred CBA; Neuronal Plasticity; Noise; Presynaptic Terminals; Synaptic Potentials
PubMed: 32747441
DOI: 10.1523/JNEUROSCI.1175-19.2020 -
Frontiers in Bioscience (Scholar... Jan 2013The mesolimbic dopamine system is an essential participant in the initiation and modulation of various forms of goal-directed behavior, including drug reinforcement and... (Review)
Review
The mesolimbic dopamine system is an essential participant in the initiation and modulation of various forms of goal-directed behavior, including drug reinforcement and addiction processes. Dopamine neurotransmission is increased by acute administration of all drugs of abuse, including the stimulants cocaine and amphetamine. Chronic exposure to these drugs via voluntary self-administration provides a model of stimulant abuse that is useful in evaluating potential behavioral and neurochemical adaptations that occur during addiction. This review describes commonly used methodologies to measure dopamine and baseline parameters of presynaptic dopamine regulation, including exocytotic release and reuptake through the dopamine transporter in the nucleus accumbens core, as well as dramatic adaptations in dopamine neurotransmission and drug sensitivity that occur with acute non-contingent and chronic, contingent self-administration of cocaine and amphetamine.
Topics: Animals; Central Nervous System Stimulants; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Illicit Drugs; Limbic System; Presynaptic Terminals; Self Administration; Synaptic Transmission
PubMed: 23277050
DOI: 10.2741/s371