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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 -
Neuroscience Dec 2015NMDA receptors (NMDARs) are glutamate-gated ion channels widely expressed in the central nervous system (CNS) and endowed with unique biophysical, pharmacological and... (Review)
Review
NMDA receptors (NMDARs) are glutamate-gated ion channels widely expressed in the central nervous system (CNS) and endowed with unique biophysical, pharmacological and signaling properties. These receptors are best known for their critical roles in synaptic plasticity and their implications in a variety of neurological and psychiatric disorders. Since their discovery three decades ago, NMDARs have been thoroughly studied as components of postsynaptic excitatory potentials. Early on, however, both anatomical and physiological evidence pointed out to the existence of NMDARs away from the postsynaptic density. Some were found to be extrasynaptic, while others seemed to be specifically present at presynaptic (i.e. axonal) elements. Although presynaptic NMDARs (preNMDARs) were at first thought to be exceptional, there is now strong evidence that these receptors are relatively widespread in the CNS and regulate synaptic strength in specific sets of synapses. In this review, we compile our current knowledge on preNMDARs, presenting their anatomical distribution, developmental regulation, subunit composition, activation mechanisms as well as their downstream effects on synapse function. Contentious issues that animate the field are also discussed. Finally, particular emphasis is put on the molecular and cellular diversity of preNMDARs which translates into a variety of effects, both short- and long-term, on synaptic efficacy. Overshadowed by their postsynaptic counterparts, preNMDARs are progressively emerging as important regulators of neuronal signaling.
Topics: Animals; Presynaptic Terminals; Receptors, N-Methyl-D-Aspartate; Receptors, Presynaptic
PubMed: 26597763
DOI: 10.1016/j.neuroscience.2015.10.033 -
European Journal of Neurology May 2022Synapse degeneration in Alzheimer's disease (AD) correlates strongly with cognitive decline. There is well-established excitatory synapse loss in AD with known...
BACKGROUND AND PURPOSE
Synapse degeneration in Alzheimer's disease (AD) correlates strongly with cognitive decline. There is well-established excitatory synapse loss in AD with known contributions of pathological amyloid beta (Aβ) to excitatory synapse dysfunction and loss. Despite clear changes in circuit excitability in AD and model systems, relatively little is known about pathology in inhibitory synapses.
METHODS
Here human postmortem brain samples (n = 5 control, 10 AD cases) from temporal and occipital cortices were examined to investigate whether inhibitory synapses and neurons are lost in AD and whether Aβ may contribute to inhibitory synapse degeneration. Inhibitory neurons were counted in all six cortical layers using stereology software, and array tomography was used to examine synapse density and the accumulation of Aβ in synaptic terminals.
RESULTS
Differing inhibitory neuron densities were observed in the different cortical layers. The highest inhibitory neuron density was observed in layer 4 in both brain regions and the visual cortex had a higher inhibitory neuron density than the temporal cortex. There was significantly lower inhibitory neuron density in AD than in control cases in all six cortical layers. High-resolution array tomography imaging revealed plaque-associated loss of inhibitory synapses and accumulation of Aβ in a small subset of inhibitory presynaptic terminals with the most accumulation near amyloid plaques.
CONCLUSIONS
Inhibitory neuron and synapse loss in AD may contribute to disrupted excitatory/inhibitory balance and cognitive decline. Future work is warranted to determine whether targeting inhibitory synapse loss could be a useful therapeutic strategy.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Humans; Plaque, Amyloid; Presynaptic Terminals; Synapses
PubMed: 34331352
DOI: 10.1111/ene.15043 -
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 -
Current Opinion in Neurobiology Jun 2023Do dendritic spines, which comprise the postsynaptic component of most excitatory synapses, exist only for their structural dynamics, receptor trafficking, and chemical... (Review)
Review
Do dendritic spines, which comprise the postsynaptic component of most excitatory synapses, exist only for their structural dynamics, receptor trafficking, and chemical and electrical compartmentation? The answer is no. Simultaneous investigation of both spine and presynaptic terminals has recently revealed a novel feature of spine synapses. Spine enlargement pushes the presynaptic terminals with muscle-like force and augments the evoked glutamate release for up to 20 min. We now summarize the evidence that such mechanical transmission shares critical features in common with short-term potentiation (STP) and may represent the cellular basis of short-term and working memory. Thus, spine synapses produce the force of learning to leave structural traces for both short and long-term memories.
Topics: Memory, Short-Term; Synapses; Presynaptic Terminals; Dendritic Spines; Hippocampus; Neuronal Plasticity
PubMed: 36931116
DOI: 10.1016/j.conb.2023.102706 -
Nature Communications Nov 2023Neuronal communication relies on the release of neurotransmitters from various populations of synaptic vesicles. Despite displaying vastly different release...
Neuronal communication relies on the release of neurotransmitters from various populations of synaptic vesicles. Despite displaying vastly different release probabilities and mobilities, the reserve and recycling pool of vesicles co-exist within a single cluster suggesting that small synaptic biomolecular condensates could regulate their nanoscale distribution. Here, we performed a large-scale activity-dependent phosphoproteome analysis of hippocampal neurons in vitro and identified Tau as a highly phosphorylated and disordered candidate protein. Single-molecule super-resolution microscopy revealed that Tau undergoes liquid-liquid phase separation to generate presynaptic nanoclusters whose density and number are regulated by activity. This activity-dependent diffusion process allows Tau to translocate into the presynapse where it forms biomolecular condensates, to selectively control the mobility of recycling vesicles. Tau, therefore, forms presynaptic nano-biomolecular condensates that regulate the nanoscale organization of synaptic vesicles in an activity-dependent manner.
Topics: Synaptic Vesicles; Biomolecular Condensates; Presynaptic Terminals; Synapses; Neurons
PubMed: 37949856
DOI: 10.1038/s41467-023-43130-4 -
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 -
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