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Experimental Biology and Medicine... May 2021An optimally functional brain requires both excitatory and inhibitory inputs that are regulated and balanced. A perturbation in the excitatory/inhibitory balance-as is... (Review)
Review
An optimally functional brain requires both excitatory and inhibitory inputs that are regulated and balanced. A perturbation in the excitatory/inhibitory balance-as is the case in some neurological disorders/diseases (e.g. traumatic brain injury Alzheimer's disease, stroke, epilepsy and substance abuse) and disorders of development (e.g. schizophrenia, Rhett syndrome and autism spectrum disorder)-leads to dysfunctional signaling, which can result in impaired cognitive and motor function, if not frank neuronal injury. At the cellular level, transmission of glutamate and GABA, the principle excitatory and inhibitory neurotransmitters in the central nervous system control excitatory/inhibitory balance. Herein, we review the synthesis, release, and signaling of GABA and glutamate followed by a focused discussion on the importance of their transport systems to the maintenance of excitatory/inhibitory balance.
Topics: Animals; Brain; Glutamic Acid; Humans; Neurons; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 33554649
DOI: 10.1177/1535370221989263 -
Cell Jan 2022Brain-derived neurotrophic factor (BDNF) is a neuropeptide that plays numerous important roles in synaptic development and plasticity. While its importance in... (Review)
Review
Brain-derived neurotrophic factor (BDNF) is a neuropeptide that plays numerous important roles in synaptic development and plasticity. While its importance in fundamental physiology is well established, studies of BDNF often produce conflicting and unclear results, and the scope of existing research makes the prospect of setting future directions daunting. In this review, we examine the importance of spatial and temporal factors on BDNF activity, particularly in processes such as synaptogenesis, Hebbian plasticity, homeostatic plasticity, and the treatment of psychiatric disorders. Understanding the fundamental physiology of when, where, and how BDNF acts and new approaches to control BDNF signaling in time and space can contribute to improved therapeutics and patient outcomes.
Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Homeostasis; Humans; Mental Disorders; Neurogenesis; Neuronal Plasticity; Neuropeptides; Psychotropic Drugs; Synapses; Synaptic Transmission; Treatment Outcome
PubMed: 34963057
DOI: 10.1016/j.cell.2021.12.003 -
Cell Feb 2023Learning has been associated with modifications of synaptic and circuit properties, but the precise changes storing information in mammals have remained largely unclear....
Learning has been associated with modifications of synaptic and circuit properties, but the precise changes storing information in mammals have remained largely unclear. We combined genetically targeted voltage imaging with targeted optogenetic activation and silencing of pre- and post-synaptic neurons to study the mechanisms underlying hippocampal behavioral timescale plasticity. In mice navigating a virtual-reality environment, targeted optogenetic activation of individual CA1 cells at specific places induced stable representations of these places in the targeted cells. Optical elicitation, recording, and modulation of synaptic transmission in behaving mice revealed that activity in presynaptic CA2/3 cells was required for the induction of plasticity in CA1 and, furthermore, that during induction of these place fields in single CA1 cells, synaptic input from CA2/3 onto these same cells was potentiated. These results reveal synaptic implementation of hippocampal behavioral timescale plasticity and define a methodology to resolve synaptic plasticity during learning and memory in behaving mammals.
Topics: Mice; Animals; CA1 Region, Hippocampal; Hippocampus; Neuronal Plasticity; Learning; Neurons; Synaptic Transmission; Mammals
PubMed: 36669484
DOI: 10.1016/j.cell.2022.12.035 -
Nature Neuroscience Jan 2020Theories stipulate that memories are encoded within networks of cortical projection neurons. Conversely, GABAergic interneurons are thought to function primarily to...
Theories stipulate that memories are encoded within networks of cortical projection neurons. Conversely, GABAergic interneurons are thought to function primarily to inhibit projection neurons and thereby impose network gain control, an important but purely modulatory role. Here we show in male mice that associative fear learning potentiates synaptic transmission and cue-specific activity of medial prefrontal cortex somatostatin (SST) interneurons and that activation of these cells controls both memory encoding and expression. Furthermore, the synaptic organization of SST and parvalbumin interneurons provides a potential circuit basis for SST interneuron-evoked disinhibition of medial prefrontal cortex output neurons and recruitment of remote brain regions associated with defensive behavior. These data suggest that, rather than constrain mnemonic processing, potentiation of SST interneuron activity represents an important causal mechanism for conditioned fear.
Topics: Animals; Association Learning; Fear; Interneurons; Male; Memory; Mice; Mice, Inbred C57BL; Prefrontal Cortex; Somatostatin; Synaptic Transmission
PubMed: 31844314
DOI: 10.1038/s41593-019-0552-7 -
Molecular Psychiatry Jan 2022The prefrontal cortex (PFC) serves as the chief executive officer of the brain, controlling the highest level cognitive and emotional processes. Its local circuits among... (Review)
Review
The prefrontal cortex (PFC) serves as the chief executive officer of the brain, controlling the highest level cognitive and emotional processes. Its local circuits among glutamatergic principal neurons and GABAergic interneurons, as well as its long-range connections with other brain regions, have been functionally linked to specific behaviors, ranging from working memory to reward seeking. The efficacy of synaptic signaling in the PFC network is profundedly influenced by monoaminergic inputs via the activation of dopamine, adrenergic, or serotonin receptors. Stress hormones and neuropeptides also exert complex effects on the synaptic structure and function of PFC neurons. Dysregulation of PFC synaptic transmission is strongly linked to social deficits, affective disturbance, and memory loss in brain disorders, including autism, schizophrenia, depression, and Alzheimer's disease. Critical neural circuits, biological pathways, and molecular players that go awry in these mental illnesses have been revealed by integrated electrophysiological, optogenetic, biochemical, and transcriptomic studies of PFC. Novel epigenetic mechanism-based strategies are proposed as potential avenues of therapeutic intervention for PFC-involved diseases. This review provides an overview of PFC network organization and synaptic modulation, as well as the mechanisms linking PFC dysfunction to the pathophysiology of neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. Insights from the preclinical studies offer the potential for discovering new medical treatments for human patients with these brain disorders.
Topics: Humans; Interneurons; Memory, Short-Term; Neurons; Prefrontal Cortex; Synaptic Transmission
PubMed: 33875802
DOI: 10.1038/s41380-021-01092-3 -
Glia Jan 2023In the last decades, astrocytes have emerged as important regulatory cells actively involved in brain function by exchanging signaling with neurons. The endocannabinoid... (Review)
Review
In the last decades, astrocytes have emerged as important regulatory cells actively involved in brain function by exchanging signaling with neurons. The endocannabinoid (eCB) signaling is widely present in many brain areas, being crucially involved in multiple brain functions and animal behaviors. The present review presents and discusses current evidence demonstrating that astrocytes sense eCBs released during neuronal activity and subsequently release gliotransmitters that regulate synaptic transmission and plasticity. The eCB signaling to astrocytes and the synaptic regulation mediated by astrocytes activated by eCBs are complex phenomena that exhibit exquisite spatial and temporal properties, a wide variety of downstream signaling mechanisms, and a large diversity of functional synaptic outcomes. Studies investigating this topic have revealed novel regulatory processes of synaptic function, like the lateral regulation of synaptic transmission and the active involvement of astrocytes in the spike-timing dependent plasticity, originally thought to be exclusively mediated by the coincident activity of pre- and postsynaptic neurons, following Hebbian rules for associative learning. Finally, the critical influence of astrocyte-mediated eCB signaling on animal behavior is also discussed.
Topics: Animals; Endocannabinoids; Neuronal Plasticity; Synaptic Transmission; Signal Transduction; Astrocytes
PubMed: 36408881
DOI: 10.1002/glia.24256 -
Nature Neuroscience Jun 2023Endocannabinoids are among the most powerful modulators of synaptic transmission throughout the nervous system, and yet little is understood about the release of...
Endocannabinoids are among the most powerful modulators of synaptic transmission throughout the nervous system, and yet little is understood about the release of endocannabinoids from postsynaptic compartments. Here we report an unexpected finding that endocannabinoid release requires synucleins, key contributors to Parkinson's disease. We show that endocannabinoids are released postsynaptically by a synuclein-dependent and SNARE-dependent mechanism. Specifically, we found that synuclein deletion blocks endocannabinoid-dependent synaptic plasticity; this block is reversed by postsynaptic expression of wild-type but not of mutant α-synuclein. Whole-cell recordings and direct optical monitoring of endocannabinoid signaling suggest that the synuclein deletion specifically blocks endocannabinoid release. Given the presynaptic role of synucleins in regulating vesicle lifecycle, we hypothesize that endocannabinoids are released via a membrane interaction mechanism. Consistent with this hypothesis, postsynaptic expression of tetanus toxin light chain, which cleaves synaptobrevin SNAREs, also blocks endocannabinoid-dependent signaling. The unexpected finding that endocannabinoids are released via a synuclein-dependent mechanism is consistent with a general function of synucleins in membrane trafficking and adds a piece to the longstanding puzzle of how neurons release endocannabinoids to induce synaptic plasticity.
Topics: Endocannabinoids; Signal Transduction; Synaptic Transmission; Neurons; Cell Communication
PubMed: 37248337
DOI: 10.1038/s41593-023-01345-0 -
Molecular and Cellular Neurosciences Mar 2023The postsynaptic density (PSD) of excitatory synapses is built from a wide variety of scaffolding proteins, receptors, and signaling molecules that collectively... (Review)
Review
The postsynaptic density (PSD) of excitatory synapses is built from a wide variety of scaffolding proteins, receptors, and signaling molecules that collectively orchestrate synaptic transmission. Seminal work over the past decades has led to the identification and functional characterization of many PSD components. In contrast, we know far less about how these constituents are assembled within synapses, and how this organization contributes to synapse function. Notably, recent evidence from high-resolution microscopy studies and in silico models, highlights the importance of the precise subsynaptic structure of the PSD for controlling the strength of synaptic transmission. Even further, activity-driven changes in the distribution of glutamate receptors are acknowledged to contribute to long-term changes in synaptic efficacy. Thus, defining the mechanisms that drive structural changes within the PSD are important for a molecular understanding of synaptic transmission and plasticity. Here, we review the current literature on how the PSD is organized to mediate basal synaptic transmission and how synaptic activity alters the nanoscale organization of synapses to sustain changes in synaptic strength.
Topics: Synapses; Synaptic Transmission; Receptors, Glutamate; Post-Synaptic Density; Nanostructures; Neuronal Plasticity
PubMed: 36720293
DOI: 10.1016/j.mcn.2023.103819 -
Neuropharmacology Jun 2022NMDA receptors play vital roles in a broad array of essential brain functions, from synaptic transmission and plasticity to learning and memory. Historically, the... (Review)
Review
NMDA receptors play vital roles in a broad array of essential brain functions, from synaptic transmission and plasticity to learning and memory. Historically, the fundamental roles of NMDARs were attributed to their specialized properties of ion flux. More recently, it has become clear that NMDARs also signal in an ion flux-independent manner. Here, we review these non-ionotropic NMDAR signaling mechanisms that have been reported to contribute to a broad array of neuronal functions and dysfunctions including synaptic transmission and plasticity, cell death and survival, and synaptic alterations associated with neurological disorders.
Topics: Learning; Neuronal Plasticity; Neurons; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Synaptic Transmission
PubMed: 35278420
DOI: 10.1016/j.neuropharm.2022.109019 -
International Journal of Molecular... Mar 2022The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors. To meet these energetic... (Review)
Review
The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors. To meet these energetic requirements, the brain primarily uses glucose, which can be metabolized through glycolysis and/or mitochondrial oxidative phosphorylation. The relevance of these two energy production pathways in fulfilling energy at presynaptic terminals has been the subject of recent studies. In this review, we dissect the balance of glycolysis and oxidative phosphorylation to meet synaptic energy demands in both resting and stimulation conditions. Besides ATP output needs, mitochondria at synapse are also important for calcium buffering and regulation of reactive oxygen species. These two mitochondrial-associated pathways, once hampered, impact negatively on neuronal homeostasis and synaptic activity. Therefore, as mitochondria assume a critical role in synaptic homeostasis, it is becoming evident that the synaptic mitochondria population possesses a distinct functional fingerprint compared to other brain mitochondria. Ultimately, dysregulation of synaptic bioenergetics through glycolytic and mitochondrial dysfunctions is increasingly implicated in neurodegenerative disorders, as one of the first hallmarks in several of these diseases are synaptic energy deficits, followed by synapse degeneration.
Topics: Animals; Brain; Energy Metabolism; Mammals; Presynaptic Terminals; Synapses; Synaptic Transmission
PubMed: 35408993
DOI: 10.3390/ijms23073627