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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 -
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 -
Current Opinion in Neurobiology Feb 2018Neuronal signaling depends on the exocytic fusion and subsequent endocytic retrieval and reformation of neurotransmitter-containing synaptic vesicles at synapses. Recent... (Review)
Review
Neuronal signaling depends on the exocytic fusion and subsequent endocytic retrieval and reformation of neurotransmitter-containing synaptic vesicles at synapses. Recent findings have uncovered surprising roles of presynaptic endocytic proteins in the formation and transport of autophagosomes. These include functions of the membrane remodelling protein endophilin and its downstream effector, the phosphoinositide phosphatase synaptojanin, in autophagosome formation and in Parkinson's disease, the endocytic sorting adaptor CALM in protein degradation via the autophagy/lysosomal pathway in Alzheimer's disease, and the clathrin adaptor complex AP-2 in retrograde transport of signaling autophagosomes to prevent neurodegeneration. These findings reveal unanticipated connections between the machineries for synaptic neurotransmission and neuronal proteostasis and identify presynaptic endocytic proteins as potential targets to treat neurodegenerative diseases.
Topics: Acyltransferases; Adaptor Proteins, Vesicular Transport; Animals; Autophagy; Endocytosis; Humans; Nerve Degeneration; Presynaptic Terminals
PubMed: 29316491
DOI: 10.1016/j.conb.2017.12.018 -
Molecules and Cells Nov 2015Synapsins were the first presynaptic proteins identified and have served as the flagship of the presynaptic protein field. Here we review recent studies demonstrating... (Review)
Review
Synapsins were the first presynaptic proteins identified and have served as the flagship of the presynaptic protein field. Here we review recent studies demonstrating that different members of the synapsin family play different roles at presynaptic terminals employing different types of synaptic vesicles. The structural underpinnings for these functions are just beginning to be understood and should provide a focus for future efforts.
Topics: Humans; Neurotransmitter Agents; Phosphorylation; Presynaptic Terminals; Protein Isoforms; Protein Transport; Synapsins; Synaptic Vesicles
PubMed: 26627875
DOI: 10.14348/molcells.2015.0233 -
Neuromolecular Medicine Sep 2017Typically, presynaptic terminals form a synapse directly on the surface of postsynaptic processes such as dendrite shafts and spines. However, some presynaptic terminals... (Review)
Review
Typically, presynaptic terminals form a synapse directly on the surface of postsynaptic processes such as dendrite shafts and spines. However, some presynaptic terminals invaginate-entirely or partially-into postsynaptic processes. We survey these invaginating presynaptic terminals in all animals and describe several examples from the central nervous system, including giant fiber systems in invertebrates, and cup-shaped spines, electroreceptor synapses, and some specialized auditory and vestibular nerve terminals in vertebrates. We then examine mechanoreceptors and photoreceptors, concentrating on the complex of pre- and postsynaptic processes found in basal invaginations of the cell. We discuss in detail the role of vertebrate invaginating horizontal cell processes in both chemical and electrical feedback mechanisms. We also discuss the common presence of indenting or invaginating terminals in neuromuscular junctions on muscles of most kinds of animals, and especially discuss those of Drosophila and vertebrates. Finally, we consider broad questions about the advantages of possessing invaginating presynaptic terminals and describe some effects of aging and disease, especially on neuromuscular junctions. We suggest that the invagination is a mechanism that can enhance both chemical and electrical interactions at the synapse.
Topics: Animals; Dendrites; Invertebrates; Mechanoreceptors; Motor Neurons; Neuromuscular Junction; Neurons, Afferent; Photoreceptor Cells; Presynaptic Terminals; Species Specificity; Synapses; Synaptic Transmission; Vertebrates
PubMed: 28612182
DOI: 10.1007/s12017-017-8445-y -
Proceedings of the Japan Academy.... 2015Classically, the basic concept of chemical synaptic transmission was established at the frog neuromuscular junction, and direct intracellular recordings from presynaptic... (Review)
Review
Classically, the basic concept of chemical synaptic transmission was established at the frog neuromuscular junction, and direct intracellular recordings from presynaptic terminals at the squid giant presynaptic terminal have further clarified principles of neurotransmitter release. More recently, whole-cell patch-camp recordings from the calyx of Held in rodent brainstem slices have extended the classical concept to mammalian synapses providing new insights into the mechanisms underlying strength and precision of neurotransmission and developmental changes therein. This review summarizes findings from our laboratory and others on these subjects, mainly at the calyx of Held, with a particular focus on precise, high-fidelity, fast neurotransmission. The mechanisms by which presynaptic terminals acquire strong, precise neurotransmission during postnatal development are also discussed.
Topics: Animals; Central Nervous System; Growth and Development; Humans; Presynaptic Terminals; Probability; Synaptic Transmission
PubMed: 26194855
DOI: 10.2183/pjab.91.305