-
Annual Review of Neuroscience Jul 2020Synaptic plasticity, the activity-dependent change in neuronal connection strength, has long been considered an important component of learning and memory. Computational... (Review)
Review
Synaptic plasticity, the activity-dependent change in neuronal connection strength, has long been considered an important component of learning and memory. Computational and engineering work corroborate the power of learning through the directed adjustment of connection weights. Here we review the fundamental elements of four broadly categorized forms of synaptic plasticity and discuss their functional capabilities and limitations. Although standard, correlation-based, Hebbian synaptic plasticity has been the primary focus of neuroscientists for decades, it is inherently limited. Three-factor plasticity rules supplement Hebbian forms with neuromodulation and eligibility traces, while true supervised types go even further by adding objectives and instructive signals. Finally, a recently discovered hippocampal form of synaptic plasticity combines the above elements, while leaving behind the primary Hebbian requirement. We suggest that the effort to determine the neural basis of adaptive behavior could benefit from renewed experimental and theoretical investigation of more powerful directed types of synaptic plasticity.
Topics: Animals; Humans; Learning; Memory; Neuronal Plasticity; Neurons; Synapses; Synaptic Transmission
PubMed: 32075520
DOI: 10.1146/annurev-neuro-090919-022842 -
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 -
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 -
Nature Neuroscience Sep 2023Social hierarchy is established as an outcome of individual social behaviors, such as dominance behavior during long-term interactions with others. Astrocytes are...
Social hierarchy is established as an outcome of individual social behaviors, such as dominance behavior during long-term interactions with others. Astrocytes are implicated in optimizing the balance between excitatory and inhibitory (E/I) neuronal activity, which may influence social behavior. However, the contribution of astrocytes in the prefrontal cortex to dominance behavior is unclear. Here we show that dorsomedial prefrontal cortical (dmPFC) astrocytes modulate E/I balance and dominance behavior in adult male mice using in vivo fiber photometry and two-photon microscopy. Optogenetic and chemogenetic activation or inhibition of dmPFC astrocytes show that astrocytes bidirectionally control male mouse dominance behavior, affecting social rank. Dominant and subordinate male mice present distinct prefrontal synaptic E/I balance, regulated by astrocyte activity. Mechanistically, we show that dmPFC astrocytes control cortical E/I balance by simultaneously enhancing presynaptic-excitatory and reducing postsynaptic-inhibitory transmission via astrocyte-derived glutamate and ATP release, respectively. Our findings show how dmPFC astrocyte-neuron communication can be involved in the establishment of social hierarchy in adult male mice.
Topics: Mice; Animals; Male; Synapses; Astrocytes; Neurons; Prefrontal Cortex; Synaptic Transmission
PubMed: 37563296
DOI: 10.1038/s41593-023-01406-4 -
Nature Structural & Molecular Biology Jul 2019
Topics: Animals; Cell Communication; Humans; Neurons; Receptors, Neurotransmitter; Synapses; Synaptic Transmission
PubMed: 31270473
DOI: 10.1038/s41594-019-0265-3 -
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 -
Nature Neuroscience Aug 2022Optogenetic actuators enable highly precise spatiotemporal interrogation of biological processes at levels ranging from the subcellular to cells, circuits and behaving... (Review)
Review
Optogenetic actuators enable highly precise spatiotemporal interrogation of biological processes at levels ranging from the subcellular to cells, circuits and behaving organisms. Although their application in neuroscience has traditionally focused on the control of spiking activity at the somatodendritic level, the scope of optogenetic modulators for direct manipulation of presynaptic functions is growing. Presynaptically localized opsins combined with light stimulation at the terminals allow light-mediated neurotransmitter release, presynaptic inhibition, induction of synaptic plasticity and specific manipulation of individual components of the presynaptic machinery. Here, we describe presynaptic applications of optogenetic tools in the context of the unique cell biology of axonal terminals, discuss their potential shortcomings and outline future directions for this rapidly developing research area.
Topics: Neuronal Plasticity; Opsins; Optogenetics; Presynaptic Terminals; Synaptic Transmission
PubMed: 35835882
DOI: 10.1038/s41593-022-01113-6