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Nature Jul 2023Whereas progress has been made in the identification of neural signals related to rapid, cued decisions, less is known about how brains guide and terminate more...
Whereas progress has been made in the identification of neural signals related to rapid, cued decisions, less is known about how brains guide and terminate more ethologically relevant decisions in which an animal's own behaviour governs the options experienced over minutes. Drosophila search for many seconds to minutes for egg-laying sites with high relative value and have neurons, called oviDNs, whose activity fulfills necessity and sufficiency criteria for initiating the egg-deposition motor programme. Here we show that oviDNs express a calcium signal that (1) dips when an egg is internally prepared (ovulated), (2) drifts up and down over seconds to minutes-in a manner influenced by the relative value of substrates-as a fly determines whether to lay an egg and (3) reaches a consistent peak level just before the abdomen bend for egg deposition. This signal is apparent in the cell bodies of oviDNs in the brain and it probably reflects a behaviourally relevant rise-to-threshold process in the ventral nerve cord, where the synaptic terminals of oviDNs are located and where their output can influence behaviour. We provide perturbational evidence that the egg-deposition motor programme is initiated once this process hits a threshold and that subthreshold variation in this process regulates the time spent considering options and, ultimately, the choice taken. Finally, we identify a small recurrent circuit that feeds into oviDNs and show that activity in each of its constituent cell types is required for laying an egg. These results argue that a rise-to-threshold process regulates a relative-value, self-paced decision and provide initial insight into the underlying circuit mechanism for building this process.
Topics: Animals; Female; Calcium Signaling; Decision Making; Drosophila melanogaster; Neural Pathways; Neurons; Oviposition; Presynaptic Terminals; Psychomotor Performance
PubMed: 37407812
DOI: 10.1038/s41586-023-06271-6 -
Neuroscience Jul 2021Editorial on Extracellular protons mediate presynaptic homeostatic potentiation at the mouse neuromuscular junction.
Editorial on Extracellular protons mediate presynaptic homeostatic potentiation at the mouse neuromuscular junction.
Topics: Animals; Homeostasis; Mice; Neuromuscular Junction; Presynaptic Terminals; Protons
PubMed: 34029647
DOI: 10.1016/j.neuroscience.2021.05.015 -
Methods in Molecular Biology (Clifton,... 2022Synaptosomes are re-sealed pinched off nerve terminals that maintain all the main structural and functional features of the original structures and that are appropriate...
Synaptosomes are re-sealed pinched off nerve terminals that maintain all the main structural and functional features of the original structures and that are appropriate to study presynaptic events. Because of the discovery of new structural and molecular events that dictate the efficiency of transmitter release and of its receptor-mediated control in the central nervous system, the interest in this tissue preparation is continuously renewing. Most of these events have been already discussed in previous reviews, but few of them were not and deserve some comments since they could suggest new functional and possibly therapeutic considerations. Among them, the "metamodulation" of receptors represents an emerging aspect that dramatically increased the complexity of the presynaptic compartment, adding new insights to the role of presynaptic receptors as modulators of chemical synapses. Deciphering the mechanism of presynaptic metamodulation would permit indirect approaches to control the activity of presynaptic release-regulating receptors that are currently orphans of direct ligands/modulators, paving the road for the proposal of new therapeutic approaches for central neurological diseases.
Topics: Central Nervous System; Presynaptic Terminals; Receptors, N-Methyl-D-Aspartate; Receptors, Presynaptic; Synapses; Synaptosomes
PubMed: 35099794
DOI: 10.1007/978-1-0716-1916-2_8 -
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 -
Pflugers Archiv : European Journal of... Sep 2021Retinal photoreceptors are neurons that convert dynamically changing patterns of light into electrical signals that are processed by retinal interneurons and ultimately... (Review)
Review
Retinal photoreceptors are neurons that convert dynamically changing patterns of light into electrical signals that are processed by retinal interneurons and ultimately transmitted to vision centers in the brain. They represent the essential first step in seeing without which the remainder of the visual system is rendered moot. To support this role, the major functions of photoreceptors are segregated into three main specialized compartments-the outer segment, the inner segment, and the pre-synaptic terminal. This compartmentalization is crucial for photoreceptor function-disruption leads to devastating blinding diseases for which therapies remain elusive. In this review, we examine the current understanding of the molecular and physical mechanisms underlying photoreceptor functional compartmentalization and highlight areas where significant knowledge gaps remain.
Topics: Animals; Cell Membrane; Humans; Photoreceptor Cells, Vertebrate; Presynaptic Terminals; Protein Transport; Retinal Neurons; Retinal Photoreceptor Cell Inner Segment; Retinal Photoreceptor Cell Outer Segment
PubMed: 33880652
DOI: 10.1007/s00424-021-02558-7 -
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 -
Cellular and Molecular Life Sciences :... Mar 2021The complex morphology of neurons, the specific requirements of synaptic neurotransmission and the accompanying metabolic demands create a unique challenge for... (Review)
Review
The complex morphology of neurons, the specific requirements of synaptic neurotransmission and the accompanying metabolic demands create a unique challenge for proteostasis. The main machineries for neuronal protein synthesis and degradation are localized in the soma, while synaptic junctions are found at vast distances from the cell body. Sophisticated mechanisms must, therefore, ensure efficient delivery of newly synthesized proteins and removal of faulty proteins. These requirements are exacerbated at presynaptic sites, where the demands for protein turnover are especially high due to synaptic vesicle release and recycling that induces protein damage in an intricate molecular machinery, and where replacement of material is hampered by the extreme length of the axon. In this review, we will discuss the contribution of the two major pathways in place, autophagy and the endolysosomal system, to presynaptic protein turnover and presynaptic function. Although clearly different in their biogenesis, both pathways are characterized by cargo collection and transport into distinct membrane-bound organelles that eventually fuse with lysosomes for cargo degradation. We summarize the available evidence with regard to their degradative function, their regulation by presynaptic machinery and the cargo for each pathway. Finally, we will discuss the interplay of both pathways in neurons and very recent findings that suggest non-canonical functions of degradative organelles in synaptic signalling and plasticity.
Topics: Animals; Autophagy; Humans; Lysosomes; Nerve Growth Factors; Neuronal Plasticity; Neurons; Presynaptic Terminals; Synapses; Synaptic Vesicles
PubMed: 33340068
DOI: 10.1007/s00018-020-03722-5 -
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