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Journal of Neurochemistry Apr 2021The synapse is formed between a presynapse (which releases neurotransmitter) and the postsynapse (which transduces this chemical signal). Over the past decade,... (Review)
Review
The synapse is formed between a presynapse (which releases neurotransmitter) and the postsynapse (which transduces this chemical signal). Over the past decade, presynaptic dysfunction has emerged as a key mediator of a series of neurodevelopmental and neurodegenerative disorders. This special issue will highlight some of the important presynaptic molecules and mechanisms that are disrupted in these conditions and reveal potential routes for therapy.
Topics: Animals; Humans; Neurodegenerative Diseases; Neurotransmitter Agents; Presynaptic Terminals; Synapses; Synaptic Vesicles
PubMed: 33728654
DOI: 10.1111/jnc.15319 -
Trends in Neurosciences Jun 2019Presynaptic boutons support neurotransmitter release with nanoscale precision at sub-millisecond timescales. Studies over the past two decades have revealed a rich... (Review)
Review
Presynaptic boutons support neurotransmitter release with nanoscale precision at sub-millisecond timescales. Studies over the past two decades have revealed a rich tapestry of molecular players governing synaptic vesicle fusion at highly specialized release sites in the active zone (AZ). However, the spatiotemporal organization of release at active synapses remains elusive, in part owing to the extremely small size of the AZ and the limited resolution of conventional approaches. Recent advances in fluorescence nanoscopy have revolutionized direct investigation of presynaptic release organization and dynamics. We discuss here recent nanoscopy-based studies of the molecular architecture, the spatial organization and dynamic regulation of release sites, and the mechanisms of release site replenishment. These findings have uncovered previously unknown levels of structural and functional organization at central synapses, with important implications for synaptic transmission and plasticity.
Topics: Animals; Exocytosis; Humans; Nanotechnology; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 31176424
DOI: 10.1016/j.tins.2019.03.001 -
Neurobiology of Disease Feb 2019Parkinson's disease (PD) is a debilitating neurodegenerative disorder that profoundly affects one's motor functions. The disease is characterized pathologically by... (Review)
Review
Parkinson's disease (PD) is a debilitating neurodegenerative disorder that profoundly affects one's motor functions. The disease is characterized pathologically by denervation of dopaminergic (DAergic) nigrostriatal terminal and degeneration of DAergic neurons in the substantia nigra par compacta (SNpc); however, the precise molecular mechanism underlying disease pathogenesis remains poorly understood. Animal studies in both toxin-induced and genetic PD models suggest that presynaptic impairments may underlie the early stage of DA depletion and neurodegeneration (reviewed in Schirinzi, T., et al. 2016). Supporting this notion, human genetic studies and genomic analysis have identified an increasing number of PD risk variants that are associated with synaptic vesicle (SV) trafficking, regulation of synaptic function and autophagy/lysosomal system (Chang, D., et al. 2017, reviewed in Trinh, J. & Farrer, M. 2013; Singleton, A.B., et al. 2013). Although the precise mechanism for autophagy regulation in neurons is currently unclear, many studies demonstrate that autophagosomes form at the presynaptic terminal (Maday, S. & Holzbaur, E.L. 2014; Vanhauwaert, R., et al. 2017; reviewed in Yue, Z. 2007). Growing evidence has revealed overlapping genes involved in both SV recycling and autophagy, suggesting that the two membrane trafficking processes are inter-connected. Here we will review emergent evidence linking SV endocytic genes and autophagy genes at the presynaptic terminal. We will discuss their potential relevance to PD pathogenesis.
Topics: Animals; Autophagy; Endocytosis; Humans; Parkinson Disease; Presynaptic Terminals; Synaptic Vesicles
PubMed: 29723605
DOI: 10.1016/j.nbd.2018.04.020 -
FEBS Letters Nov 2018In presynaptic nerve terminals, synaptic vesicles are recycled locally via an evolutionarily conserved process that ensures maintenance of neurotransmission as well as... (Review)
Review
In presynaptic nerve terminals, synaptic vesicles are recycled locally via an evolutionarily conserved process that ensures maintenance of neurotransmission as well as structural integrity of synapses. Temperature is a key environmental factor that impacts critical steps involved in fusion, endocytosis and transport in different vesicle trafficking pathways. In neurons, temperature changes have been shown to impact synaptic vesicle recycling and synaptic efficacy. But contrary to non-neuronal systems, the temperature dependence of the steps involved in fusion, endocytosis and recycling of synaptic vesicles in presynaptic terminals is not completely understood, and the existing data remain highly debated. In this Review, we discuss the implications of biophysical, biochemical and functional findings on temperature dependence of membrane retrieval in multiple systems. We propose that systematic investigation of the temperature dependence of the presynaptic vesicle trafficking process can provide novel insight into poorly understood mechanisms that govern synaptic vesicle trafficking under diverse physiological conditions.
Topics: Animals; Endocytosis; Humans; Neurons; Presynaptic Terminals; Synapses; Synaptic Transmission; Synaptic Vesicles; Temperature; Time Factors
PubMed: 30311950
DOI: 10.1002/1873-3468.13268 -
Cells Oct 2022The concept of the tripartite synapse describes the close interaction of pre- and postsynaptic elements and the surrounding astrocyte processes. For glutamatergic...
The concept of the tripartite synapse describes the close interaction of pre- and postsynaptic elements and the surrounding astrocyte processes. For glutamatergic synapses, it is established that the presence of astrocytic processes and their structural arrangements varies considerably between and within brain regions and between synapses of the same neuron. In contrast, less is known about the organization of astrocytic processes at GABAergic synapses although bi-directional signaling is known to exist at these synapses too. Therefore, we established super-resolution expansion microscopy of GABAergic synapses and nearby astrocytic processes in the of the mouse hippocampal CA1 region. By visualizing the presynaptic vesicular GABA transporter and the postsynaptic clustering protein gephyrin, we documented the subsynaptic heterogeneity of GABAergic synaptic contacts. We then compared the volume distribution of astrocytic processes near GABAergic synapses between individual synapses and with glutamatergic synapses. We made two novel observations. First, astrocytic processes were more abundant at the GABAergic synapses with large postsynaptic gephyrin clusters. Second, astrocytic processes were less abundant in the vicinity of GABAergic synapses compared to glutamatergic, suggesting that the latter may be selectively approached by astrocytes. Because of the GABA transporter distribution, we also speculate that this specific arrangement enables more efficient re-uptake of GABA into presynaptic terminals.
Topics: Animals; GABA Plasma Membrane Transport Proteins; Mice; Presynaptic Terminals; Receptors, GABA-A; Synapses; gamma-Aminobutyric Acid
PubMed: 36231112
DOI: 10.3390/cells11193150 -
Neuron Jan 2021Neurons are highly polarized cells with a single axon and multiple dendrites derived from the cell body to form tightly associated pre- and postsynaptic compartments. As... (Review)
Review
Neurons are highly polarized cells with a single axon and multiple dendrites derived from the cell body to form tightly associated pre- and postsynaptic compartments. As the biosynthetic machinery is largely restricted to the somatodendritic domain, the vast majority of presynaptic components are synthesized in the neuronal soma, packaged into synaptic precursor vesicles, and actively transported along the axon to sites of presynaptic biogenesis. In contrast with the significant progress that has been made in understanding synaptic transmission and processing of information at the post-synapse, comparably little is known about the formation and dynamic remodeling of the presynaptic compartment. We review here our current understanding of the mechanisms that govern the biogenesis, transport, and assembly of the key components for presynaptic neurotransmission, discuss how alterations in presynaptic assembly may impact nervous system function or lead to disease, and outline key open questions for future research.
Topics: Animals; Humans; Neurogenesis; Presynaptic Terminals; Protein Transport; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 33098763
DOI: 10.1016/j.neuron.2020.09.038 -
Neuroscience Jan 2018The rodent whisker-to-barrel cortex pathway is a classic model to study the effects of sensory experience and deprivation on neuronal circuit formation, not only during... (Review)
Review
The rodent whisker-to-barrel cortex pathway is a classic model to study the effects of sensory experience and deprivation on neuronal circuit formation, not only during development but also in the adult. Decades of research have produced a vast body of evidence highlighting the fundamental role of neuronal activity (spontaneous and/or sensory-evoked) for circuit formation and function. In this context, it has become clear that neuronal adaptation and plasticity is not just a function of the neonatal brain, but persists into adulthood, especially after experience-driven modulation of network status. Mechanisms for structural remodeling of the somatodendritic or axonal domain include microscale alterations of neurites or synapses. At the same time, functional alterations at the nanoscale such as expression or activation changes of channels and receptors contribute to the modulation of intrinsic excitability or input-output relationships. However, it remains elusive how these forms of structural and functional plasticity come together to shape neuronal network formation and function. While specifically somatodendritic plasticity has been studied in great detail, the role of axonal plasticity, (e.g. at presynaptic boutons, branches or axonal microdomains), is rather poorly understood. Therefore, this review will only briefly highlight somatodendritic plasticity and instead focus on axonal plasticity. We discuss (i) the role of spontaneous and sensory-evoked plasticity during critical periods, (ii) the assembly of axonal presynaptic sites, (iii) axonal plasticity in the mature brain under baseline and sensory manipulation conditions, and finally (iv) plasticity of electrogenic axonal microdomains, namely the axon initial segment, during development and in the mature CNS.
Topics: Animals; Axons; Nerve Net; Neuronal Plasticity; Presynaptic Terminals; Rodentia; Somatosensory Cortex
PubMed: 28739523
DOI: 10.1016/j.neuroscience.2017.07.035 -
Pharmacological Reviews Apr 2017Presynaptic nerve terminals are highly specialized vesicle-trafficking machines. Neurotransmitter release from these terminals is sustained by constant local recycling... (Review)
Review
Presynaptic nerve terminals are highly specialized vesicle-trafficking machines. Neurotransmitter release from these terminals is sustained by constant local recycling of synaptic vesicles independent from the neuronal cell body. This independence places significant constraints on maintenance of synaptic protein complexes and scaffolds. Key events during the synaptic vesicle cycle-such as exocytosis and endocytosis-require formation and disassembly of protein complexes. This extremely dynamic environment poses unique challenges for proteostasis at synaptic terminals. Therefore, it is not surprising that subtle alterations in synaptic vesicle cycle-associated proteins directly or indirectly contribute to pathophysiology seen in several neurologic and psychiatric diseases. In contrast to the increasing number of examples in which presynaptic dysfunction causes neurologic symptoms or cognitive deficits associated with multiple brain disorders, synaptic vesicle-recycling machinery remains an underexplored drug target. In addition, irrespective of the involvement of presynaptic function in the disease process, presynaptic machinery may also prove to be a viable therapeutic target because subtle alterations in the neurotransmitter release may counter disease mechanisms, correct, or compensate for synaptic communication deficits without the need to interfere with postsynaptic receptor signaling. In this article, we will overview critical properties of presynaptic release machinery to help elucidate novel presynaptic avenues for the development of therapeutic strategies against neurologic and neuropsychiatric disorders.
Topics: Animals; Endocytosis; Exocytosis; Humans; Presynaptic Terminals; Synaptic Vesicles
PubMed: 28265000
DOI: 10.1124/pr.116.013342 -
Current Opinion in Neurobiology Apr 2017Each presynaptic bouton is densely packed with many vesicles, only a small fraction of which are available for immediate release. These vesicles constitute the readily... (Review)
Review
Each presynaptic bouton is densely packed with many vesicles, only a small fraction of which are available for immediate release. These vesicles constitute the readily releasable pool (RRP). The RRP size, and the probability of release of each vesicle within the RRP, together determine synaptic strength. Here, we discuss complications and recent advances in determining the size of the physiologically relevant RRP. We consider molecular mechanisms to generate and regulate the RRP, and discuss the relationship between vesicle docking and the RRP. We conclude that many RRP vesicles are docked, that some docked vesicles may not be part of the RRP, and that undocked vesicles can contribute to the RRP by rapid recruitment to unoccupied, molecularly activated ready-to-release sites.
Topics: Humans; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 28103533
DOI: 10.1016/j.conb.2016.12.012 -
Journal of Neurochemistry Apr 2021Parkinson's disease is a common neurodegenerative disorder and is clinically characterized by bradykinesia, rigidity, and resting tremor. Missense mutations in the... (Review)
Review
Parkinson's disease is a common neurodegenerative disorder and is clinically characterized by bradykinesia, rigidity, and resting tremor. Missense mutations in the leucine-rich repeat protein kinase-2 gene (LRRK2) are a recognized cause of inherited Parkinson's disease. The physiological and pathological impact of LRRK2 is still obscure, but accumulating evidence indicates that LRRK2 orchestrates diverse aspects of membrane trafficking, such as membrane fusion and vesicle formation and transport along actin and tubulin tracks. In the present review, we focus on the special relation between LRRK2 and synaptic vesicles. LRRK2 binds and phosphorylates key actors within the synaptic vesicle cycle. Accordingly, alterations in dopamine and glutamate transmission have been described upon LRRK2 manipulations. However, the different modeling strategies and phenotypes observed require a critical approach to decipher the outcome of LRRK2 at the pre-synaptic site.
Topics: Animals; Endocytosis; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Neurons; Parkinson Disease; Presynaptic Terminals; Synaptic Vesicles
PubMed: 33206398
DOI: 10.1111/jnc.15240