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International Journal of Molecular... May 2022Unrelated genetic mutations can lead to convergent manifestations of neurological disorders with similar behavioral phenotypes. Experimental data frequently show a lack... (Review)
Review
Unrelated genetic mutations can lead to convergent manifestations of neurological disorders with similar behavioral phenotypes. Experimental data frequently show a lack of dramatic changes in neuroanatomy, indicating that the key cause of symptoms might arise from impairment in the communication between neurons. A transient imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) synaptic transmission (the E/I balance) during early development is generally considered to underlie the development of several neurological disorders in adults. However, the E/I ratio is a multidimensional variable. Synaptic contacts are highly dynamic and the actual strength of synaptic projections is determined from the balance between synaptogenesis and synaptic elimination. During development, relatively slow postsynaptic receptors are replaced by fast ones that allow for fast stimulus-locked excitation/inhibition. Using the binomial model of synaptic transmission allows for the reassessing of experimental data from different mouse models, showing that a transient E/I shift is frequently counterbalanced by additional pre- and/or postsynaptic changes. Such changes-for instance, the slowing down of postsynaptic currents by means of immature postsynaptic receptors-stabilize the average synaptic strength, but impair the timing of information flow. Compensatory processes and/or astrocytic signaling may represent possible targets for medical treatments of different disorders directed to rescue the proper information processing.
Topics: Animals; Astrocytes; Excitatory Postsynaptic Potentials; Mice; Neurons; Signal Transduction; Synaptic Transmission
PubMed: 35628556
DOI: 10.3390/ijms23105746 -
Current Opinion in Neurobiology Aug 2019Nervous systems are built on synaptic connections, and our understanding of these complex compartments has deepened over the past quarter century as the diverse fields... (Review)
Review
Nervous systems are built on synaptic connections, and our understanding of these complex compartments has deepened over the past quarter century as the diverse fields of genetics, molecular biology, physiology, and biochemistry each made significant in-roads into synaptic function. On the presynaptic side, an evolutionarily conserved core fusion apparatus constructed from a handful of proteins has emerged, with Unc13 serving as a hub that coordinates nearly every aspect of synaptic transmission. This review briefly highlights recent studies on diverse aspects of Unc13 function including roles in SNARE assembly and quality control, release site building, calcium channel proximity, and short-term synaptic plasticity.
Topics: Neuronal Plasticity; SNARE Proteins; Synaptic Transmission
PubMed: 30690332
DOI: 10.1016/j.conb.2018.12.011 -
Neuroscience Feb 2021Astrocytes, a major type of glial cell, are known to play key supportive roles in brain function, contributing to ion and neurotransmitter homeostasis, maintaining the... (Review)
Review
Astrocytes, a major type of glial cell, are known to play key supportive roles in brain function, contributing to ion and neurotransmitter homeostasis, maintaining the blood-brain barrier and providing trophic and metabolic support for neurons. Besides these support functions, astrocytes are emerging as important elements in brain physiology through signaling exchange with neurons at tripartite synapses. Astrocytes express a wide variety of neurotransmitter transporters and receptors that allow them to sense and respond to synaptic activity. Principal among them are the G-protein-coupled receptors (GPCRs) in astrocytes because their activation by synaptically released neurotransmitters leads to mobilization of intracellular calcium. In turn, activated astrocytes release neuroactive substances called gliotransmitters, such as glutamate, GABA, and ATP/adenosine that lead to synaptic regulation through activation of neuronal GPCRs. In this review we will present and discuss recent evidence demonstrating the critical roles played by GPCRs in the bidirectional astrocyte-neuron signaling, and their crucial involvement in the astrocyte-mediated regulation of synaptic transmission and plasticity.
Topics: Astrocytes; Cell Communication; Neurons; Receptors, G-Protein-Coupled; Synapses; Synaptic Transmission
PubMed: 32224231
DOI: 10.1016/j.neuroscience.2020.03.025 -
Molecular Psychiatry Jan 2022Drug addiction remains a key biomedical challenge facing current neuroscience research. In addition to neural mechanisms, the focus of the vast majority of studies to... (Review)
Review
Drug addiction remains a key biomedical challenge facing current neuroscience research. In addition to neural mechanisms, the focus of the vast majority of studies to date, astrocytes have been increasingly recognized as an "accomplice." According to the tripartite synapse model, astrocytes critically regulate nearby pre- and postsynaptic neuronal substrates to craft experience-dependent synaptic plasticity, including synapse formation and elimination. Astrocytes within brain regions that are implicated in drug addiction exhibit dynamic changes in activity upon exposure to cocaine and subsequently undergo adaptive changes themselves during chronic drug exposure. Recent results have identified several key astrocytic signaling pathways that are involved in cocaine-induced synaptic and circuit adaptations. In this review, we provide a brief overview of the role of astrocytes in regulating synaptic transmission and neuronal function, and discuss how cocaine influences these astrocyte-mediated mechanisms to induce persistent synaptic and circuit alterations that promote cocaine seeking and relapse. We also consider the therapeutic potential of targeting astrocytic substrates to ameliorate drug-induced neuroplasticity for behavioral benefits. While primarily focusing on cocaine-induced astrocytic responses, we also include brief discussion of other drugs of abuse where data are available.
Topics: Astrocytes; Cocaine-Related Disorders; Humans; Neuronal Plasticity; Synapses; Synaptic Transmission
PubMed: 33837268
DOI: 10.1038/s41380-021-01080-7 -
ELife Dec 2021Rapid and precise neuronal communication is enabled through a highly synchronous release of signaling molecules neurotransmitters within just milliseconds of the action...
Rapid and precise neuronal communication is enabled through a highly synchronous release of signaling molecules neurotransmitters within just milliseconds of the action potential. Yet neurotransmitter release lacks a theoretical framework that is both phenomenologically accurate and mechanistically realistic. Here, we present an analytic theory of the action-potential-triggered neurotransmitter release at the chemical synapse. The theory is demonstrated to be in detailed quantitative agreement with existing data on a wide variety of synapses from electrophysiological recordings and fluorescence experiments . Despite up to ten orders of magnitude of variation in the release rates among the synapses, the theory reveals that synaptic transmission obeys a simple, universal scaling law, which we confirm through a collapse of the data from strikingly diverse synapses onto a single master curve. This universality is complemented by the capacity of the theory to readily extract, through a fit to the data, the kinetic and energetic parameters that uniquely identify each synapse. The theory provides a means to detect cooperativity among the SNARE complexes that mediate vesicle fusion and reveals such cooperativity in several existing data sets. The theory is further applied to establish connections between molecular constituents of synapses and synaptic function. The theory allows competing hypotheses of short-term plasticity to be tested and identifies the regimes where particular mechanisms of synaptic facilitation dominate or, conversely, fail to account for the existing data for the paired-pulse ratio. The derived trade-off relation between the transmission rate and fidelity shows how transmission failure can be controlled by changing the microscopic properties of the vesicle pool and SNARE complexes. The established condition for the maximal synaptic efficacy reveals that no fine tuning is needed for certain synapses to maintain near-optimal transmission. We discuss the limitations of the theory and propose possible routes to extend it. These results provide a quantitative basis for the notion that the molecular-level properties of synapses are crucial determinants of the computational and information-processing functions in synaptic transmission.
Topics: Action Potentials; Animals; Neurotransmitter Agents; Synapses; Synaptic Transmission
PubMed: 34970965
DOI: 10.7554/eLife.73585 -
Neuroscience Nov 2019Vti proteins are conserved from yeast to humans and regulate intracellular membrane trafficking by providing one specific SNARE domain, the Qb SNARE, to the four helical... (Review)
Review
Vti proteins are conserved from yeast to humans and regulate intracellular membrane trafficking by providing one specific SNARE domain, the Qb SNARE, to the four helical SNARE bundle that drives membrane fusion. Two mammalian Vti genes, Vti1a and Vti1b are reported to regulate distinct aspects of endolysosomal trafficking and retrograde transport to the Golgi, but have also been implicated in synaptic vesicle secretion. In this review, we summarize the current evidence for the role of Vti proteins in intracellular trafficking in different cells. We propose that, despite some unique aspects, the two mammalian VTI genes have largely redundant functions in neurosecretory cells and recycle molecules required for the sorting of regulated cargo to the Golgi. Defects in this recycling also lead to defects in synaptic transmission and dense core vesicle secretion.
Topics: Animals; Exocytosis; Humans; Lysosomes; Neurons; Protein Transport; Qb-SNARE Proteins; Synaptic Transmission
PubMed: 30471354
DOI: 10.1016/j.neuroscience.2018.11.014 -
ACS Chemical Neuroscience Apr 2024Serotonin (5-HT) is a vital modulatory neurotransmitter responsible for regulating most behaviors in the brain. An inefficient 5-HT synaptic function is often linked to... (Review)
Review
Serotonin (5-HT) is a vital modulatory neurotransmitter responsible for regulating most behaviors in the brain. An inefficient 5-HT synaptic function is often linked to various mental disorders. Primarily, membrane proteins controlling the expression and activity of 5-HT synthesis, storage, release, receptor activation, and inactivation are critical to 5-HT signaling in synaptic and extra-synaptic sites. Moreover, these signals represent information transmission across membranes. Although the lipid membrane environment is often viewed as fairly stable, emerging research suggests significant functional lipid-protein interactions with many synaptic 5-HT proteins. These protein-lipid interactions extend to almost all the primary lipid classes that form the plasma membrane. Collectively, these lipid classes and lipid-protein interactions affect 5-HT synaptic efficacy at the synapse. The highly dynamic lipid composition of synaptic membranes suggests that these lipids and their interactions with proteins may contribute to the plasticity of the 5-HT synapse. Therefore, this broader protein-lipid model of the 5-HT synapse necessitates a reconsideration of 5-HT's role in various associated mental disorders.
Topics: Humans; Serotonin; Signal Transduction; Synapses; Cell Membrane; Lipids; Synaptic Transmission
PubMed: 38499042
DOI: 10.1021/acschemneuro.3c00823 -
International Journal of Molecular... May 2024Dopamine is a key neurotransmitter involved in physiological processes such as motor control, motivation, reward, cognitive function, and maternal and reproductive... (Review)
Review
Dopamine is a key neurotransmitter involved in physiological processes such as motor control, motivation, reward, cognitive function, and maternal and reproductive behaviors. Therefore, dysfunctions of the dopaminergic system are related to a plethora of human diseases. Dopamine, via different circuitries implicated in compulsive behavior, reward, and habit formation, also represents a key player in substance use disorder and the formation and perpetuation of mechanisms leading to addiction. Here, we propose dopamine as a model not only of neurotransmission but also of neuromodulation capable of modifying neuronal architecture. Abuse of substances like methamphetamine, cocaine, and alcohol and their consumption over time can induce changes in neuronal activities. These modifications lead to synaptic plasticity and finally to morphological and functional changes, starting from maladaptive neuro-modulation and ending in neurodegeneration.
Topics: Humans; Dopamine; Animals; Substance-Related Disorders; Neuronal Plasticity; Synaptic Transmission
PubMed: 38791331
DOI: 10.3390/ijms25105293 -
The FEBS Journal Nov 2020The cerebellum, a universal processor for sensory acquisition and internal models, and its association with synaptic and nonsynaptic plasticity have been envisioned as... (Review)
Review
The cerebellum, a universal processor for sensory acquisition and internal models, and its association with synaptic and nonsynaptic plasticity have been envisioned as the biological correlates of learning, perception, and even thought. Indeed, the cerebellum is no longer considered merely as the locus of motor coordination and its learning. Here, we introduce the mechanisms underlying the induction of multiple types of plasticity in cerebellar circuit and give an overview focusing on the plasticity of nonsynaptic intrinsic excitability. The discovery of long-term potentiation of synaptic responsiveness in hippocampal neurons led investigations into changes of their intrinsic excitability. This activity-dependent potentiation of neuronal excitability is distinct from that of synaptic efficacy. Systematic examination of excitability plasticity has indicated that the modulation of various types of Ca - and voltage-dependent K channels underlies the phenomenon, which is also triggered by immune activity. Intrinsic plasticity is expressed specifically on dendrites and modifies the integrative processing and filtering effect. In Purkinje cells, modulation of the discordance of synaptic current on soma and dendrite suggested a novel type of cellular learning mechanism. This property enables a plausible synergy between synaptic efficacy and intrinsic excitability, by amplifying electrical conductivity and influencing the polarity of bidirectional synaptic plasticity. Furthermore, the induction of intrinsic plasticity in the cerebellum correlates with motor performance and cognitive processes, through functional connections from the cerebellar nuclei to neocortex and associated regions: for example, thalamus and midbrain. Taken together, recent advances in neuroscience have begun to shed light on the complex functioning of nonsynaptic excitability and the synergy.
Topics: Animals; Cerebellum; Cerebral Cortex; Excitatory Postsynaptic Potentials; Hippocampus; Humans; Long-Term Potentiation; Neuronal Plasticity; Neurons; Synaptic Transmission
PubMed: 32367676
DOI: 10.1111/febs.15355 -
Trends in Neurosciences Apr 2023Neuronal communication crucially relies on exocytosis of neurotransmitters from synaptic vesicles (SVs) which are clustered at synapses. To ensure reliable... (Review)
Review
Neuronal communication crucially relies on exocytosis of neurotransmitters from synaptic vesicles (SVs) which are clustered at synapses. To ensure reliable neurotransmitter release, synapses need to maintain an adequate pool of SVs at all times. Decades of research have established that SVs are clustered by synapsin 1, an abundant SV-associated phosphoprotein. The classical view postulates that SVs are crosslinked in a scaffold of protein-protein interactions between synapsins and their binding partners. Recent studies have shown that synapsins cluster SVs via liquid-liquid phase separation (LLPS), thus providing a new framework for the organization of the synapse. We discuss the evidence for phase separation of SVs, emphasizing emerging questions related to its regulation, specificity, and reversibility.
Topics: Humans; Synaptic Vesicles; Synapsins; Synapses; Synaptic Transmission; Biology
PubMed: 36725404
DOI: 10.1016/j.tins.2023.01.001