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The Journal of Neuroscience : the... Feb 2022Stable neural function requires an energy supply that can meet the intense episodic power demands of neuronal activity. Neurons have presumably optimized the volume of...
Stable neural function requires an energy supply that can meet the intense episodic power demands of neuronal activity. Neurons have presumably optimized the volume of their bioenergetic machinery to ensure these power demands are met, but the relationship between presynaptic power demands and the volume available to the bioenergetic machinery has never been quantified. Here, we estimated the power demands of six motor nerve terminals in female larvae through direct measurements of neurotransmitter release and Ca entry, and via theoretical estimates of Na entry and power demands at rest. Electron microscopy revealed that terminals with the highest power demands contained the greatest volume of mitochondria, indicating that mitochondria are allocated according to presynaptic power demands. In addition, terminals with the greatest power demand-to-volume ratio (∼66 nmol·min·µl) harbor the largest mitochondria packed at the greatest density. If we assume sequential and complete oxidation of glucose by glycolysis and oxidative phosphorylation, then these mitochondria are required to produce ATP at a rate of 52 nmol·min·µl at rest, rising to 963 during activity. Glycolysis would contribute ATP at 0.24 nmol·min·µl of cytosol at rest, rising to 4.36 during activity. These data provide a quantitative framework for presynaptic bioenergetics , and reveal that, beyond an immediate capacity to accelerate ATP output from glycolysis and oxidative phosphorylation, over longer time periods presynaptic terminals optimize mitochondrial volume and density to meet power demand. The remarkable energy demands of the brain are supported by the complete oxidation of its fuel but debate continues regarding a division of labor between glycolysis and oxidative phosphorylation across different cell types. Here, we exploit the neuromuscular synapse, a model for studying neurophysiology, to elucidate fundamental aspects of neuronal energy metabolism that ultimately constrain rates of neural processing. We quantified energy production rates required to sustain activity at individual nerve terminals and compared these with the volume capable of oxidative phosphorylation (mitochondria) and glycolysis (cytosol). We find strong support for oxidative phosphorylation playing a primary role in presynaptic terminals and provide the first estimates of energy production rates per unit volume of presynaptic mitochondria and cytosol.
Topics: Animals; Brain; Drosophila; Energy Metabolism; Female; Mitochondria; Mitochondrial Size; Motor Neurons; Presynaptic Terminals; Synaptic Transmission
PubMed: 34907026
DOI: 10.1523/JNEUROSCI.1236-21.2021 -
Current Opinion in Neurobiology Aug 2020In a presynaptic nerve terminal, the active zone is composed of sophisticated protein machinery that enables secretion on a submillisecond time scale and precisely... (Review)
Review
In a presynaptic nerve terminal, the active zone is composed of sophisticated protein machinery that enables secretion on a submillisecond time scale and precisely targets it toward postsynaptic receptors. The past two decades have provided deep insight into the roles of active zone proteins in exocytosis, but we are only beginning to understand how a neuron assembles active zone protein complexes into effective molecular machines. In this review, we outline the fundamental processes that are necessary for active zone assembly and discuss recent advances in understanding assembly mechanisms that arise from genetic, morphological and biochemical studies. We further outline the challenges ahead for understanding this important problem.
Topics: Exocytosis; Neurons; Presynaptic Terminals; Proteins; Synapses
PubMed: 32403081
DOI: 10.1016/j.conb.2020.03.008 -
Proceedings of the National Academy of... Mar 2021For neuronal circuits in the brain to mature, necessary synapses must be maintained and redundant synapses eliminated through experience-dependent mechanisms. However,...
For neuronal circuits in the brain to mature, necessary synapses must be maintained and redundant synapses eliminated through experience-dependent mechanisms. However, the functional differentiation of these synapse types during the refinement process remains elusive. Here, we addressed this issue by distinct labeling and direct recordings of presynaptic terminals fated for survival and for elimination in the somatosensory thalamus. At surviving terminals, the number of total releasable vesicles was first enlarged, and then calcium channels and fast-releasing synaptic vesicles were tightly coupled in an experience-dependent manner. By contrast, transmitter release mechanisms did not mature at terminals fated for elimination, irrespective of sensory experience. Nonetheless, terminals fated for survival and for elimination both exhibited developmental shortening of action potential waveforms that was experience independent. Thus, we dissected experience-dependent and -independent developmental maturation processes of surviving and eliminated presynaptic terminals during neuronal circuit refinement.
Topics: Action Potentials; Afferent Pathways; Animals; Calcium Channels; Mice; Nerve Net; Neurotransmitter Agents; Presynaptic Terminals; Synaptic Vesicles; Trigeminal Nuclei; Ventral Thalamic Nuclei; Vibrissae
PubMed: 33688051
DOI: 10.1073/pnas.2022423118 -
Biological Chemistry Apr 2023In the CNS communication between neurons occurs at synapses by secretion of neurotransmitter via exocytosis of synaptic vesicles (SVs) at the active zone. Given the... (Review)
Review
In the CNS communication between neurons occurs at synapses by secretion of neurotransmitter via exocytosis of synaptic vesicles (SVs) at the active zone. Given the limited number of SVs in presynaptic boutons a fast and efficient recycling of exocytosed membrane and proteins by triggered compensatory endocytosis is required to maintain neurotransmission. Thus, pre-synapses feature a unique tight coupling of exo- and endocytosis in time and space resulting in the reformation of SVs with uniform morphology and well-defined molecular composition. This rapid response requires early stages of endocytosis at the peri-active zone to be well choreographed to ensure reformation of SVs with high fidelity. The pre-synapse can address this challenge by a specialized membrane microcompartment, where a pre-sorted and pre-assembled readily retrievable pool (RRetP) of endocytic membrane patches is formed, consisting of the vesicle cargo, presumably bound within a nucleated Clathrin and adaptor complex. This review considers evidence for the RRetP microcompartment to be the primary organizer of presynaptic triggered compensatory endocytosis.
Topics: Synaptic Vesicles; Synapses; Synaptic Transmission; Neurons; Presynaptic Terminals; Endocytosis; Exocytosis
PubMed: 36867726
DOI: 10.1515/hsz-2022-0298 -
Biomolecules Mar 2022α-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson's disease (PD), dementia with Lewy bodies... (Review)
Review
α-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Alzheimer's Disease (AD). In normal physiology, α-syn plays a pivotal role in facilitating endocytosis and exocytosis. Interestingly, mutations and modifications of precise α-syn domains interfere with α-syn oligomerization and nucleation that negatively affect presynaptic vesicular dynamics, protein expressions, and mitochondrial profiles. Furthermore, the integration of the α-syn oligomers into the presynaptic membrane results in pore formations, ion influx, and excitotoxicity. Targeted therapies against specific domains of α-syn, including the use of small organic molecules, monoclonal antibodies, and synthetic peptides, are being screened and developed. However, the prospect of an effective α-syn targeted therapy is still plagued by low permeability across the blood-brain barrier (BBB), and poor entry into the presynaptic axon terminals. The present review proposes a modification of current strategies, which includes the use of novel encapsulation technology, such as lipid nanoparticles, to bypass the BBB and deliver such agents into the brain.
Topics: Humans; Liposomes; Nanoparticles; Parkinson Disease; Presynaptic Terminals; alpha-Synuclein
PubMed: 35454096
DOI: 10.3390/biom12040507 -
Neuron Nov 2017At each of the brain's vast number of synapses, the presynaptic nerve terminal, synaptic cleft, and postsynaptic specialization form a transcellular unit to enable... (Review)
Review
At each of the brain's vast number of synapses, the presynaptic nerve terminal, synaptic cleft, and postsynaptic specialization form a transcellular unit to enable efficient transmission of information between neurons. While we know much about the molecular machinery within each compartment, we are only beginning to understand how these compartments are structurally registered and functionally integrated with one another. This review will describe the organization of each compartment and then discuss their alignment across pre- and postsynaptic cells at a nanometer scale. We propose that this architecture may allow for precise synaptic information exchange and may be modulated to contribute to the remarkable plasticity of brain function.
Topics: Animals; Cell Communication; Exocytosis; Humans; Neuronal Plasticity; Presynaptic Terminals; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 29096080
DOI: 10.1016/j.neuron.2017.10.006 -
Current Opinion in Structural Biology Feb 2019Neurotransmitter release at the presynaptic terminal is one of the fundamental processes in neuronal communication. It is a complex process comprising signaling pathways... (Review)
Review
Neurotransmitter release at the presynaptic terminal is one of the fundamental processes in neuronal communication. It is a complex process comprising signaling pathways that exert a precise spatio-temporal coordination to prepare and bring synaptic vesicles to exocytosis. While many molecular components involved have been identified, their direct observation at different stages of the neurotransmitter release is lacking. Three-dimensional imaging by electron tomography provided remarkable views of the synaptic vesicles and the cytomatrix. Imaging fully hydrated, vitrified samples allowed a direct visualization, precise localization and a quantitative characterization of pleomorphic synaptic vesicle-bound complexes in situ, as well as the elucidation of their function in the neurotransmitter release.
Topics: Animals; Cryoelectron Microscopy; Neurotransmitter Agents; Presynaptic Terminals
PubMed: 30925443
DOI: 10.1016/j.sbi.2019.01.008 -
Trends in Neurosciences Sep 2018The ability of central synapses to undergo long-term potentiation (LTP) still captures the imagination of scientists and has become one of the most fascinating and... (Review)
Review
The ability of central synapses to undergo long-term potentiation (LTP) still captures the imagination of scientists and has become one of the most fascinating and deeply studied questions in modern neuroscience. By the mid-1990s, however, the field was deeply ensnarled in trying to answer a passionately dichotomous question: is LTP expressed by a pre- or a postsynaptic mechanism? Experimental results that could only be seen by many as being incontrovertibly contradictory presented a perplexing conundrum. However, two papers published in 1995 fundamentally redefined critical assumptions and provided a cunningly simple and elegant solution to an otherwise inextricable impasse.
Topics: Animals; Long-Term Potentiation; Post-Synaptic Density; Presynaptic Terminals; Synapses
PubMed: 30143180
DOI: 10.1016/j.tins.2018.07.002 -
Current Opinion in Neurobiology Aug 2018Research over the past half a century has revealed remarkable diversity among chemical synapses of the CNS. The structural, functional and molecular diversity of... (Review)
Review
Research over the past half a century has revealed remarkable diversity among chemical synapses of the CNS. The structural, functional and molecular diversity of synapses was mainly concluded from studying different synapses in distinct brain regions and preparations. It is not surprising that synapses made by molecularly distinct pre-synaptic and post-synaptic cells display different morphological and functional properties with distinct underlying molecular mechanisms. However, synapses made by a single presynaptic cell onto distinct types of postsynaptic cells, or distinct presynaptic inputs onto a single postsynaptic cell, also show remarkable heterogeneity. Here, by reviewing recent experiments, I suggest that robust functional diversity can be achieved by building synapses from the same molecules, but using different numbers, densities and nanoscale arrangements.
Topics: Animals; Brain; Calcium; Neurotransmitter Agents; Presynaptic Terminals; Synapses; Synaptic Membranes
PubMed: 29353084
DOI: 10.1016/j.conb.2018.01.001 -
Current Opinion in Neurobiology Aug 2018Presynaptic nerve terminals release neurotransmitter synchronously, asynchronously or spontaneously. During synchronous neurotransmission release is precisely coupled to... (Review)
Review
Presynaptic nerve terminals release neurotransmitter synchronously, asynchronously or spontaneously. During synchronous neurotransmission release is precisely coupled to action potentials, in contrast, asynchronous release events show only loose temporal coupling to presynaptic activity whereas spontaneous neurotransmission occurs independent of presynaptic activity. The mechanisms that give rise to this diversity in neurotransmitter release modes are poorly understood. Recent studies have described several presynaptic molecular pathways controlling synaptic vesicle pool segregation and recycling, which in turn may dictate distinct modes of neurotransmitter release. In this article, we review this recent work regarding neurotransmitter release modes and their relationship to synaptic vesicle pool dynamics as well as the molecular machinery that establishes synaptic vesicle pool identity.
Topics: Action Potentials; Animals; Models, Neurological; Neurons; Neurotransmitter Agents; Presynaptic Terminals; Synaptic Vesicles
PubMed: 29597140
DOI: 10.1016/j.conb.2018.03.005