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Alcoholism, Clinical and Experimental... Jan 2020Alcohol addiction causes major health problems throughout the world, causing numerous deaths and incurring a huge economic burden to society. To develop an intervention... (Review)
Review
Alcohol addiction causes major health problems throughout the world, causing numerous deaths and incurring a huge economic burden to society. To develop an intervention for alcohol addiction, it is necessary to identify molecular target(s) of alcohol and associated molecular mechanisms of alcohol action. The functions of many central and peripheral synapses are impacted by low concentrations of ethanol (EtOH). While the postsynaptic targets and mechanisms are studied extensively, there are limited studies on the presynaptic targets and mechanisms. This article is an endeavor in this direction, focusing on the effect of EtOH on the presynaptic proteins associated with the neurotransmitter release machinery. Studies on the effects of EtOH at the levels of gene, protein, and behavior are highlighted in this article.
Topics: Alcoholism; Animals; Ethanol; Humans; Presynaptic Terminals; Protein Structure, Secondary; Protein Structure, Tertiary; SNARE Proteins; Synapses; Synaptic Transmission
PubMed: 31724225
DOI: 10.1111/acer.14238 -
Function (Oxford, England) 2021Voltage-gated calcium channels are the principal conduits for depolarization-mediated Ca entry into excitable cells. In this review, the biophysical properties of the... (Review)
Review
Voltage-gated calcium channels are the principal conduits for depolarization-mediated Ca entry into excitable cells. In this review, the biophysical properties of the relevant members of this family of channels, those that are present in presynaptic terminals, will be discussed in relation to their function in mediating neurotransmitter release. Voltage-gated calcium channels have properties that ensure they are specialized for particular roles, for example, differences in their activation voltage threshold, their various kinetic properties, and their voltage-dependence of inactivation. All these attributes play into the ability of the various voltage-gated calcium channels to participate in different patterns of presynaptic vesicular release. These include synaptic transmission resulting from single action potentials, and longer-term changes mediated by bursts or trains of action potentials, as well as release resulting from graded changes in membrane potential in specialized sensory synapses.
Topics: Presynaptic Terminals; Calcium Channels; Synaptic Transmission; Synapses; Action Potentials
PubMed: 33313507
DOI: 10.1093/function/zqaa027 -
Neuron Nov 2022Presynaptic homeostatic plasticity (PHP) adaptively regulates synaptic transmission in health and disease. Despite identification of numerous genes that are essential...
Presynaptic homeostatic plasticity (PHP) adaptively regulates synaptic transmission in health and disease. Despite identification of numerous genes that are essential for PHP, we lack a dynamic framework to explain how PHP is initiated, potentiated, and limited to achieve precise control of vesicle fusion. Here, utilizing both mice and Drosophila, we demonstrate that PHP progresses through the assembly and physical expansion of presynaptic signaling foci where activated integrins biochemically converge with trans-synaptic Semaphorin2b/PlexinB signaling. Each component of the identified signaling complexes, including alpha/beta-integrin, Semaphorin2b, PlexinB, talin, and focal adhesion kinase (FAK), and their biochemical interactions, are essential for PHP. Complex integrity requires the Sema2b ligand and complex expansion includes a ∼2.5-fold expansion of active-zone associated puncta composed of the actin-binding protein talin. Finally, complex pre-expansion is sufficient to accelerate the rate and extent of PHP. A working model is proposed incorporating signal convergence with dynamic molecular assemblies that instruct PHP.
Topics: Animals; Mice; Drosophila Proteins; Drosophila melanogaster; Presynaptic Terminals; Talin; Neuronal Plasticity; Drosophila
PubMed: 36087584
DOI: 10.1016/j.neuron.2022.08.016 -
Neuron Aug 2022Learning and memory rely on long-lasting, synapse-specific modifications. Although postsynaptic forms of plasticity typically require local protein synthesis, whether...
Learning and memory rely on long-lasting, synapse-specific modifications. Although postsynaptic forms of plasticity typically require local protein synthesis, whether and how local protein synthesis contributes to presynaptic changes remain unclear. Here, we examined the mouse hippocampal mossy fiber (MF)-CA3 synapse, which expresses both structural and functional presynaptic plasticity and contains presynaptic fragile X messenger ribonucleoprotein (FMRP), an RNA-binding protein involved in postsynaptic protein-synthesis-dependent plasticity. We report that MF boutons contain ribosomes and synthesize protein locally. The long-term potentiation of MF-CA3 synaptic transmission (MF-LTP) was associated with the translation-dependent enlargement of MF boutons. Remarkably, increasing in vitro or in vivo MF activity enhanced the protein synthesis in MFs. Moreover, the deletion of presynaptic FMRP blocked structural and functional MF-LTP, suggesting that FMRP is a critical regulator of presynaptic MF plasticity. Thus, presynaptic FMRP and protein synthesis dynamically control presynaptic structure and function in the mature mammalian brain.
Topics: Animals; Fragile X Mental Retardation Protein; Long-Term Potentiation; Mammals; Mice; Mossy Fibers, Hippocampal; Neuronal Plasticity; Presynaptic Terminals; Ribonucleoproteins; Synapses
PubMed: 35728596
DOI: 10.1016/j.neuron.2022.05.024 -
Pharmacology & Therapeutics Nov 2022Glutamate is the primary excitatory neurotransmitter in the brain and plays critical roles in all aspects of neuronal function. Disruption of normal glutamate... (Review)
Review
Glutamate is the primary excitatory neurotransmitter in the brain and plays critical roles in all aspects of neuronal function. Disruption of normal glutamate transmission has been implicated in a variety of neurodegenerative and neuropsychiatric diseases. Glutamate exerts its effect through ionotropic and metabotropic glutamate receptors (mGluRs). mGluR2 and mGluR3 are members of the Group II mGluR family and their activation leads to the inhibition of glutamate release from presynaptic nerve terminals and is also poised upstream of a myriad of signaling pathways in postsynaptic nerve terminals and neuroglia. Therefore, mGluR2 and mGluR3 have been considered as potential drug targets for the treatment of many neurological conditions and several compounds targeting these receptors have been developed. In this review, we discuss what is currently known regarding the contribution of mGluR2 and mGluR3 to the pathophysiology of some neurodegenerative and neuropsychiatric diseases including Amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's diseases, schizophrenia and depression as well as drug addiction. We then highlight the evidence supporting the use of various drugs including orthosteric and allosteric ligands acting on either mGluR2, mGluR3 or both for the management of these brain disorders.
Topics: Humans; Receptors, Metabotropic Glutamate; Presynaptic Terminals; Glutamic Acid; Neurons
PubMed: 36038019
DOI: 10.1016/j.pharmthera.2022.108275 -
Progress in Neurobiology Nov 2020Synaptic loss is the best correlate of cognitive deficits in Alzheimer's disease (AD). Extensive experimental evidence also indicates alterations of synaptic properties... (Review)
Review
Synaptic loss is the best correlate of cognitive deficits in Alzheimer's disease (AD). Extensive experimental evidence also indicates alterations of synaptic properties at the early stages of disease progression, before synapse loss and neuronal degeneration. A majority of studies in mouse models of AD have focused on post-synaptic mechanisms, including impairment of long-term plasticity, spine structure and glutamate receptor-mediated transmission. Here we review the literature indicating that the synaptic pathology in AD includes a strong presynaptic component. We describe the evidence indicating presynaptic physiological functions of the major molecular players in AD. These include the amyloid precursor protein (APP) and the two presenilin (PS) paralogs PS1 or PS2, genetically linked to the early-onset form of AD, in addition to tau which accumulates in a pathological form in the AD brain. Three main mechanisms participating in presynaptic functions are highlighted. APP fragments bind to presynaptic receptors (e.g. nAChRs and GABA receptors), presenilins control Ca homeostasis and Ca-sensors, and tau regulates the localization of presynaptic molecules and synaptic vesicles. We then discuss how impairment of these presynaptic physiological functions can explain or forecast the hallmarks of synaptic impairment and associated dysfunction of neuronal circuits in AD. Beyond the physiological roles of the AD-related proteins, studies in AD brains also support preferential presynaptic alteration. This review features presynaptic failure as a strong component of pathological mechanisms in AD.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Humans; Presenilins; Presynaptic Terminals; Receptors, Presynaptic; Synaptic Transmission; tau Proteins
PubMed: 32428558
DOI: 10.1016/j.pneurobio.2020.101801 -
Hearing Research Mar 2023Fragile X mental retardation protein (FMRP) binds a selected set of mRNAs and proteins to guide neural circuit assembly and regulate synaptic plasticity. Loss of FMRP is... (Review)
Review
Fragile X mental retardation protein (FMRP) binds a selected set of mRNAs and proteins to guide neural circuit assembly and regulate synaptic plasticity. Loss of FMRP is responsible for Fragile X syndrome, a neuropsychiatric disorder characterized with auditory processing problems and social difficulty. FMRP actions in synaptic formation, maturation, and plasticity are site-specific among the four compartments of a synapse: presynaptic and postsynaptic neurons, astrocytes, and extracellular matrix. This review summarizes advancements in understanding FMRP localization, signals, and functional roles in axons and presynaptic terminals.
Topics: Axons; Fragile X Mental Retardation Protein; Neurons; Presynaptic Terminals; Synapses; Humans
PubMed: 36809742
DOI: 10.1016/j.heares.2023.108720 -
The Journal of Neuroscience : the... Nov 2023Local protein synthesis in mature brain axons regulates the structure and function of presynaptic boutons by adjusting the presynaptic proteome to local demands. This...
Local protein synthesis in mature brain axons regulates the structure and function of presynaptic boutons by adjusting the presynaptic proteome to local demands. This crucial mechanism underlies experience-dependent modifications of brain circuits, and its dysregulation may contribute to brain disorders, such as autism and intellectual disability. Here, we discuss recent advancements in the axonal transcriptome, axonal RNA localization and translation, and the role of presynaptic local translation in synaptic plasticity and memory.
Topics: Axons; Presynaptic Terminals; Neuronal Plasticity; Brain
PubMed: 37940588
DOI: 10.1523/JNEUROSCI.1454-23.2023 -
Neuroscience Feb 2021In this review we will discuss the effect of two neuromodulatory transmitters, acetylcholine (ACh) and adenosine, on the synaptic release probability and short-term... (Review)
Review
In this review we will discuss the effect of two neuromodulatory transmitters, acetylcholine (ACh) and adenosine, on the synaptic release probability and short-term synaptic plasticity. ACh and adenosine differ fundamentally in the way they are released into the extracellular space. ACh is released mostly from synaptic terminals and axonal bouton of cholinergic neurons in the basal forebrain (BF). Its mode of action on synaptic release probability is complex because it activate both ligand-gated ion channels, so-called nicotinic ACh receptors and G-protein coupled muscarinic ACh receptors. In contrast, adenosine is released from both neurons and glia via nucleoside transporters or diffusion over the cell membrane in a non-vesicular, non-synaptic fashion; its receptors are exclusively G-protein coupled receptors. We show that ACh and adenosine effects are highly specific for an identified synaptic connection and depend mostly on the presynaptic but also on the postsynaptic receptor type and discuss the functional implications of these differences.
Topics: Acetylcholine; Cholinergic Agents; Presynaptic Terminals; Receptors, Muscarinic; Receptors, Nicotinic; Synaptic Transmission
PubMed: 32540364
DOI: 10.1016/j.neuroscience.2020.06.006 -
Biomolecules Jan 2022Synaptic transmission is essential for controlling motor functions and maintaining brain functions such as walking, breathing, cognition, learning, and memory.... (Review)
Review
Synaptic transmission is essential for controlling motor functions and maintaining brain functions such as walking, breathing, cognition, learning, and memory. Neurotransmitter release is regulated by presynaptic molecules assembled in active zones of presynaptic terminals. The size of presynaptic terminals varies, but the size of a single active zone and the types of presynaptic molecules are highly conserved among neuromuscular junctions (NMJs) and central synapses. Three parameters play an important role in the determination of neurotransmitter release properties at NMJs and central excitatory/inhibitory synapses: the number of presynaptic molecular clusters, the protein families of the presynaptic molecules, and the distance between presynaptic molecules and voltage-gated calcium channels. In addition, dysfunction of presynaptic molecules causes clinical symptoms such as motor and cognitive decline in patients with various neurological disorders and during aging. This review focuses on the molecular mechanisms responsible for the functional similarities and differences between excitatory and inhibitory synapses in the peripheral and central nervous systems, and summarizes recent findings regarding presynaptic molecules assembled in the active zone. Furthermore, we discuss the relationship between functional alterations of presynaptic molecules and dysfunction of NMJs or central synapses in diseases and during aging.
Topics: Aging; Humans; Neuromuscular Junction; Presynaptic Terminals; Synapses; Synaptic Transmission
PubMed: 35204679
DOI: 10.3390/biom12020179