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Neurobiology of Disease Jan 2022Huntington's disease (HD) is a heritable, fatal neurodegenerative disorder caused by a mutation in the Huntingtin gene. It is characterized by chorea, as well as... (Review)
Review
Huntington's disease (HD) is a heritable, fatal neurodegenerative disorder caused by a mutation in the Huntingtin gene. It is characterized by chorea, as well as cognitive and psychiatric symptoms. Histopathologically, there is a massive loss of striatal projection neurons and less but significant loss in other areas throughout the cortico-basal ganglia-thalamocortical (CBGTC) loop. The mutant huntingtin protein has been implicated in numerous functions, including an important role in synaptic transmission. Most studies on anatomical and physiological alterations in HD have focused on striatum and cerebral cortex. However, based on recent CBGTC projectome evidence, the need to study other pathways has become increasingly clear. In this review, we examine the current status of our knowledge of morphological and electrophysiological alterations of those pathways in animal models of HD. Based on recent studies, there is accumulating evidence that synaptic disconnection, particularly along excitatory pathways, is pervasive and almost universal in HD, thus supporting a critical role of the huntingtin protein in synaptic transmission.
Topics: Animals; Cerebral Cortex; Corpus Striatum; Disease Models, Animal; Huntingtin Protein; Huntington Disease; Synaptic Transmission
PubMed: 34848336
DOI: 10.1016/j.nbd.2021.105574 -
Neuroscience Letters Nov 2019In the early 1950s, Katz and his colleagues capitalized on the newly developed intracellular microelectrode recording technique to investigate synaptic transmission. For... (Review)
Review
In the early 1950s, Katz and his colleagues capitalized on the newly developed intracellular microelectrode recording technique to investigate synaptic transmission. For study they chose frog neuromuscular junction (NMJ), which was ideally suited due to the accessibility and large size of the muscle cells. Paradoxically, the large size precluded the use of next generation patch clamp technology. Consequently, electrophysiological study of synaptic function shifted to small central synapses made amenable by patch clamp. Recently, however, the unique features offered by zebrafish have rekindled interest in the NMJ as a model for electrophysiological study of synaptic transmission. The small muscle size and synaptic simplicity provide the singular opportunity to perform in vivo spinal motoneuron-target muscle patch clamp recordings. Additional incentive is provided by zebrafish lines harboring mutations in key synaptic proteins, many of which are embryonic lethal in mammals, but all of which are able to survive well past synapse maturation in zebrafish. This mini-review will highlight features that set zebrafish NMJs apart from traditional NMJs. We also draw into focus findings that offer the promise of identifying features that define release sites, which serve to set the upper limit of transmitter release. Since its conception several candidates representing release sites have been proposed, most of which are based on distinctions among vesicle pools in their state of readiness for release. However, models based on distinctions among vesicles have become enormously complicated and none adequately account for setting an upper limit for exocytosis in response to an action potential (AP). Specifically, findings from zebrafish NMJ point to an alternative model, positing that elements other than vesicles per se set the upper limits of release.
Topics: Animals; Long-Term Synaptic Depression; Neuromuscular Junction; Neurotransmitter Agents; Synaptic Transmission; Synaptic Vesicles; Zebrafish
PubMed: 31557523
DOI: 10.1016/j.neulet.2019.134503 -
Journal of Pharmacy & Pharmaceutical... 2021Neurons are special polarized cells whose synaptic vesicles release neurotransmitters into the synaptic cleft, acting on postsynaptic receptors and thus transmitting... (Review)
Review
Neurons are special polarized cells whose synaptic vesicles release neurotransmitters into the synaptic cleft, acting on postsynaptic receptors and thus transmitting information from presynaptic to postsynaptic states. The integrity of the vesicle cycle is critical to the transmission of neural signals in the brain. According to the molecular mechanism of calcium-triggered release, the assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) is required in the process of synaptic vesicle fusion and vesicle exocytosis. Many delicate steps are required to maintain the dynamic process of 'release-recycle', including intermediate processes and the dynamic balance of neurotransmission. Various neurodegenerative and neuropsychiatric diseases result from synaptic cycle dysfunction. This review of the relationships between the structure and function of synaptic vesicles in physiological and pathological conditions provides a theoretical basis for synaptic transmission and a novel avenue for the study of synaptic plasticity associated with mood disorders, highlighting potential targets for treating diseases.
Topics: Animals; Calcium; Exocytosis; Humans; Nervous System Diseases; Neuronal Plasticity; Neurons; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 34343470
DOI: 10.18433/jpps31458 -
Science Advances Jun 2023Synaptic vesicle tethering, priming, and neurotransmitter release require a coordinated action of multiple protein complexes. While physiological experiments,...
Synaptic vesicle tethering, priming, and neurotransmitter release require a coordinated action of multiple protein complexes. While physiological experiments, interaction data, and structural studies of purified systems were essential for our understanding of the function of the individual complexes involved, they cannot resolve how the actions of individual complexes integrate. We used cryo-electron tomography to simultaneously image multiple presynaptic protein complexes and lipids at molecular resolution in their native composition, conformation, and environment. Our detailed morphological characterization suggests that sequential synaptic vesicle states precede neurotransmitter release, where Munc13-comprising bridges localize vesicles <10 nanometers and soluble -ethylmaleimide-sensitive factor attachment protein 25-comprising bridges <5 nanometers from the plasma membrane, the latter constituting a molecularly primed state. Munc13 activation supports the transition to the primed state via vesicle bridges to plasma membrane (tethers), while protein kinase C promotes the same transition by reducing vesicle interlinking. These findings exemplify a cellular function performed by an extended assembly comprising multiple molecularly diverse complexes.
Topics: Synaptic Vesicles; Synaptic Transmission; Membrane Fusion; Cell Membrane; Neurotransmitter Agents
PubMed: 37343100
DOI: 10.1126/sciadv.adf6222 -
Cerebral Cortex (New York, N.Y. : 1991) Apr 2023Microcircuits in the neocortex are functionally organized along layers and columns, which are the fundamental modules of cortical information processing. While the...
Microcircuits in the neocortex are functionally organized along layers and columns, which are the fundamental modules of cortical information processing. While the function of cortical microcircuits has focused on neuronal elements, much less is known about the functional organization of astrocytes and their bidirectional interaction with neurons. Here, we show that Cannabinoid type 1 receptor (CB1R)-mediated astrocyte activation by neuron-released endocannabinoids elevate astrocyte Ca2+ levels, stimulate ATP/adenosine release as gliotransmitters, and transiently depress synaptic transmission in layer 5 pyramidal neurons at relatively distant synapses (˃20 μm) from the stimulated neuron. This astrocyte-mediated heteroneuronal synaptic depression occurred between pyramidal neurons within a cortical column and was absent in neurons belonging to adjacent cortical columns. Moreover, this form of heteroneuronal synaptic depression occurs between neurons located in particular layers, following a specific connectivity pattern that depends on a layer-specific neuron-to-astrocyte signaling. These results unravel the existence of astrocyte-mediated nonsynaptic communication between cortical neurons and that this communication is column- and layer-specific, which adds further complexity to the intercellular signaling processes in the neocortex.
Topics: Astrocytes; Somatosensory Cortex; Neurons; Synaptic Transmission; Signal Transduction; Synapses
PubMed: 36124663
DOI: 10.1093/cercor/bhac357 -
Seminars in Cell & Developmental Biology May 2023Dendritic spines are small protrusions arising from dendrites and constitute the major compartment of excitatory post-synapses. They change in number, shape, and size... (Review)
Review
Dendritic spines are small protrusions arising from dendrites and constitute the major compartment of excitatory post-synapses. They change in number, shape, and size throughout life; these changes are thought to be associated with formation and reorganization of neuronal networks underlying learning and memory. As spines in the brain are surrounded by the microenvironment including neighboring cells and the extracellular matrix, their protrusion requires generation of force to push against these structures. In turn, neighboring cells receive force from protruding spines. Recent studies have identified BAR-domain proteins as being involved in membrane deformation to initiate spine formation. In addition, forces for dendritic filopodium extension and activity-induced spine expansion are generated through cooperation between actin polymerization and clutch coupling. On the other hand, force from expanding spines affects neurotransmitter release from presynaptic terminals. Here, we review recent advances in our understanding of the physical aspects of synapse formation and plasticity, mainly focusing on spine dynamics.
Topics: Dendritic Spines; Synaptic Transmission; Neurons; Synapses; Neuronal Plasticity
PubMed: 35659473
DOI: 10.1016/j.semcdb.2022.05.017 -
Journal of Neurochemistry Aug 2019Huntington disease (HD) is an inherited neurodegenerative disorder caused by an expansion of the CAG repeat region in the first exon of the huntingtin gene.... (Review)
Review
Huntington disease (HD) is an inherited neurodegenerative disorder caused by an expansion of the CAG repeat region in the first exon of the huntingtin gene. Neurodegeneration, which begins in the striatum and then spreads to other brain areas, is preceded by dysfunction in multiple aspects of neurotransmission across a variety of brain areas. This review will provide an overview of the neurochemical mediators and modulators of synaptic transmission that are disrupted in HD. This includes classical neurotransmitters like glutamate and gamma-aminobutyric acid, modulators such as dopamine, adenosine and endocannabinoids, and molecules like brain-derived neurotrophic factor which affect neurotransmission in a more indirect manner. Alterations in the functioning of these signaling pathways can occur across multiple brain regions such as striatum, cortex and hippocampus, and affect transmission and plasticity at the synapses within these regions, which may ultimately change behaviour and contribute to the pathophysiology of HD. The current state of knowledge in this area has already yielded useful information about the causes of synaptic dysfunction and selective cell death. A full understanding of the mechanisms and consequences of disruptions in synaptic function and plasticity will lend insight into the development of the symptoms of HD, and potential drug targets for ameliorating them.
Topics: Animals; Humans; Huntington Disease; Neuronal Plasticity; Synaptic Transmission
PubMed: 31095731
DOI: 10.1111/jnc.14723 -
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 -
Preface: Cholinergic mechanisms: This is the Preface for the special issue "Cholinergic Mechanisms".Journal of Neurochemistry Sep 2021This special issue of the Journal of Neurochemistry, entitled "Cholinergic Mechanisms," presents 15 reviews and two original papers, which have been selected to cover...
This special issue of the Journal of Neurochemistry, entitled "Cholinergic Mechanisms," presents 15 reviews and two original papers, which have been selected to cover the broad spectrum of topics and disciplines presented at the XVIth International Symposium on Cholinergic Mechanisms (ISCM-XVI), ranging from the molecular and the cellular to the clinical and the cognitive mechanisms of cholinergic transmission. The authors discuss recent developments in the field, for instance, the association of cholinergic transmission with a number of important neurological and neuromuscular diseases in the central and peripheral nervous systems.
Topics: Acetylcholine; Animals; Brain; Cholinergic Agents; Cholinergic Neurons; Humans; Peripheral Nervous System; Synaptic Transmission
PubMed: 34458988
DOI: 10.1111/jnc.15480 -
Current Opinion in Neurobiology Jun 2022As synaptic vesicles fuse, they must continually be replaced with new docked, fusion-competent vesicles to sustain neurotransmission. It has long been appreciated that... (Review)
Review
As synaptic vesicles fuse, they must continually be replaced with new docked, fusion-competent vesicles to sustain neurotransmission. It has long been appreciated that vesicles are recruited to docking sites in an activity-dependent manner. However, once entering the sites, vesicles were thought to be stably docked, awaiting calcium signals. Based on recent data from electrophysiology, electron microscopy, biochemistry, and computer simulations, a picture emerges in which vesicles can rapidly and reversibly transit between docking and undocking during activity. This "transient docking" can account for many aspects of synaptic physiology. In this review, we cover recent evidence for transient docking, physiological processes at the synapse that it may support, and progress on the underlying mechanisms. We also discuss an open question: what determines for how long and whether vesicles stay docked, or eventually undock?
Topics: Computer Simulation; Microscopy, Electron; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 35398664
DOI: 10.1016/j.conb.2022.102535