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Brain, Behavior, and Immunity Jan 2024Cytokines are potent immunomodulators exerting pleiotropic effects in the central nervous system (CNS). They influence neuronal functions and circuit activities with...
Cytokines are potent immunomodulators exerting pleiotropic effects in the central nervous system (CNS). They influence neuronal functions and circuit activities with effects on memory processes and behaviors. Here, we unravel a neuromodulatory activity of interleukin-15 (IL-15) in mouse brain. Acute exposure of hippocampal slices to IL-15 enhances gamma-aminobutyricacid (GABA) release and reduces glutamatergic currents, while chronic treatment with IL-15 increases the frequency of hippocampal miniature inhibitory synaptic transmission and impairs memory formation in the novel object recognition (NOR) test. Moreover, we describe that serotonin is involved in mediating the hippocampal effects of IL-15, because a selective 5-HTA receptor antagonist prevents the effects on inhibitory neurotransmission and ameliorates mice performance in the NOR test. These findings provide new insights into the modulatory activities of cytokines in the CNS, with implications on behavior.
Topics: Mice; Animals; Interleukin-15; Memory, Episodic; Hippocampus; Synaptic Transmission; Neurons
PubMed: 37992787
DOI: 10.1016/j.bbi.2023.11.015 -
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 -
International Journal of Molecular... Feb 2024One of the most biologically relevant functions of astrocytes within the CNS is the regulation of synaptic transmission, i.e., the physiological basis for information... (Review)
Review
One of the most biologically relevant functions of astrocytes within the CNS is the regulation of synaptic transmission, i.e., the physiological basis for information transmission between neurons. Changes in the strength of synaptic connections are indeed thought to be the cellular basis of learning and memory. Importantly, astrocytes have been demonstrated to tightly regulate these processes via the release of several gliotransmitters linked to astrocytic calcium activity as well as astrocyte-neuron metabolic coupling. Therefore, astrocytes seem to be integrators of and actors upon learning- and memory-relevant information. In this review, we focus on the role of astrocytes in learning and memory processes. We delineate the recognized inputs and outputs of astrocytes and explore the influence of manipulating astrocytes on behaviour across diverse learning paradigms. We conclude that astrocytes influence learning and memory in various manners. Appropriate astrocytic Ca dynamics are being increasingly identified as central contributors to memory formation and retrieval. In addition, astrocytes regulate brain rhythms essential for cognition, and astrocyte-neuron metabolic cooperation is required for memory consolidation.
Topics: Astrocytes; Learning; Synaptic Transmission; Neurons; Memory
PubMed: 38339177
DOI: 10.3390/ijms25031899 -
Physiological Reviews Jan 2022Chemical synapses are commonly known as a structurally and functionally highly diverse class of cell-cell contacts specialized to mediate communication between neurons.... (Review)
Review
Chemical synapses are commonly known as a structurally and functionally highly diverse class of cell-cell contacts specialized to mediate communication between neurons. They represent the smallest "computational" unit of the brain and are typically divided into excitatory and inhibitory as well as modulatory categories. These categories are subdivided into diverse types, each representing a different structure-function repertoire that in turn are thought to endow neuronal networks with distinct computational properties. The diversity of structure and function found among a given category of synapses is referred to as heterogeneity. The main building blocks for this heterogeneity are synaptic vesicles, the active zone, the synaptic cleft, the postsynaptic density, and glial processes associated with the synapse. Each of these five structural modules entails a distinct repertoire of functions, and their combination specifies the range of functional heterogeneity at mammalian excitatory synapses, which are the focus of this review. We describe synapse heterogeneity that is manifested on different levels of complexity ranging from the cellular morphology of the pre- and postsynaptic cells toward the expression of different protein isoforms at individual release sites. We attempt to define the range of structural building blocks that are used to vary the basic functional repertoire of excitatory synaptic contacts and discuss sources and general mechanisms of synapse heterogeneity. Finally, we explore the possible impact of synapse heterogeneity on neuronal network function.
Topics: Animals; Glutamates; Humans; Neuronal Plasticity; Neurons; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 34727002
DOI: 10.1152/physrev.00039.2020 -
The Journal of Neuroscience : the... Apr 2022The presynaptic action potential (AP) is required to drive calcium influx into nerve terminals, resulting in neurotransmitter release. Accordingly, the AP waveform is...
The presynaptic action potential (AP) is required to drive calcium influx into nerve terminals, resulting in neurotransmitter release. Accordingly, the AP waveform is crucial in determining the timing and strength of synaptic transmission. The calyx of Held nerve terminals of rats of either sex showed minimum changes in AP waveform during high-frequency AP firing. We found that the stability of the calyceal AP waveform requires KCNQ (K7) K channel activation during high-frequency spiking activity. High-frequency presynaptic spikes gradually led to accumulation of KCNQ channels in open states which kept interspike membrane potential sufficiently negative to maintain Na channel availability. Blocking KCNQ channels during stimulus trains led to inactivation of presynaptic Na, and to a lesser extent K1 channels, thereby reducing the AP amplitude and broadening AP duration. Moreover, blocking KCNQ channels disrupted the stable calcium influx and glutamate release required for reliable synaptic transmission at high frequency. Thus, while KCNQ channels are generally thought to prevent hyperactivity of neurons, we find that in axon terminals these channels function to facilitate reliable high-frequency synaptic signaling needed for sensory information processing. The presynaptic spike results in calcium influx required for neurotransmitter release. For this reason, the spike waveform is crucial in determining the timing and strength of synaptic transmission. Auditory information is encoded by spikes phase locked to sound frequency at high rates. The calyx of Held nerve terminals in the auditory brainstem show minimum changes in spike waveform during high-frequency spike firing. We found that activation of KCNQ K channel builds up during high-frequency firing and its activation helps to maintain a stable spike waveform and reliable synaptic transmission. While KCNQ channels are generally thought to prevent hyperexcitability of neurons, we find that in axon terminals these channels function to facilitate high-frequency synaptic signaling during auditory information processing.
Topics: Action Potentials; Animals; Calcium; Neurotransmitter Agents; Presynaptic Terminals; Rats; Sodium; Synaptic Transmission
PubMed: 35256530
DOI: 10.1523/JNEUROSCI.0363-20.2022 -
Communications Biology Dec 2023The brain consists of the left and right cerebral hemispheres and both are connected by callosal projections. Less is known about the basic mechanism of this...
The brain consists of the left and right cerebral hemispheres and both are connected by callosal projections. Less is known about the basic mechanism of this cortical-cortical connection and its functional importance. Here we investigate the cortical-cortical connection between the bilateral anterior cingulate cortex (ACC) by using the classic electrophysiological and optogenetic approach. We find that there is a direct synaptic projection from one side ACC to the contralateral ACC. Glutamate is the major excitatory transmitter for bilateral ACC connection, including projections to pyramidal cells in superficial (II/III) and deep (V/VI) layers of the ACC. Both AMPA and kainate receptors contribute to synaptic transmission. Repetitive stimulation of the projection also evoked postsynaptic Ca influx in contralateral ACC pyramidal neurons. Behaviorally, light activation of the ACC-ACC connection facilitated behavioral withdrawal responses to mechanical stimuli and noxious heat. In an animal model of neuropathic pain, light inhibitory of ACC-ACC connection reduces both primary and secondary hyperalgesia. Our findings provide strong direct evidence for the excitatory or facilitatory contribution of ACC-ACC connection to pain perception, and this mechanism may provide therapeutic targets for future treatment of chronic pain and related emotional disorders.
Topics: Mice; Animals; Gyrus Cinguli; Synaptic Transmission; Neuralgia; Pyramidal Cells; Glutamic Acid
PubMed: 38071375
DOI: 10.1038/s42003-023-05589-1 -
Cells Feb 2024Neurotransmission occurs within highly specialized compartments forming the active synapse where the complex organization and dynamics of the interactions are tightly... (Review)
Review
Neurotransmission occurs within highly specialized compartments forming the active synapse where the complex organization and dynamics of the interactions are tightly orchestrated both in time and space. Post-translational modifications (PTMs) are central to these spatiotemporal regulations to ensure an efficient synaptic transmission. SUMOylation is a dynamic PTM that modulates the interactions between proteins and consequently regulates the conformation, the distribution and the trafficking of the SUMO-target proteins. SUMOylation plays a crucial role in synapse formation and stabilization, as well as in the regulation of synaptic transmission and plasticity. In this review, we summarize the molecular consequences of this protein modification in the structural organization and function of the mammalian synapse. We also outline novel activity-dependent regulation and consequences of the SUMO process and explore how this protein modification can functionally participate in the compartmentalization of both pre- and post-synaptic sites.
Topics: Animals; Sumoylation; Protein Processing, Post-Translational; Small Ubiquitin-Related Modifier Proteins; Synaptic Transmission; Mammals; Synapses
PubMed: 38474384
DOI: 10.3390/cells13050420 -
Nature Communications Dec 2022Acutely silencing specific neurons informs about their functional roles in circuits and behavior. Existing optogenetic silencers include ion pumps, channels,...
Acutely silencing specific neurons informs about their functional roles in circuits and behavior. Existing optogenetic silencers include ion pumps, channels, metabotropic receptors, and tools that damage the neurotransmitter release machinery. While the former hyperpolarize the cell, alter ionic gradients or cellular biochemistry, the latter allow only slow recovery, requiring de novo synthesis. Thus, tools combining fast activation and reversibility are needed. Here, we use light-evoked homo-oligomerization of cryptochrome CRY2 to silence synaptic transmission, by clustering synaptic vesicles (SVs). We benchmark this tool, optoSynC, in Caenorhabditis elegans, zebrafish, and murine hippocampal neurons. optoSynC clusters SVs, observable by electron microscopy. Locomotion silencing occurs with tau ~7.2 s and recovers with tau ~6.5 min after light-off. optoSynC can inhibit exocytosis for several hours, at very low light intensities, does not affect ion currents, biochemistry or synaptic proteins, and may further allow manipulating different SV pools and the transfer of SVs between them.
Topics: Animals; Mice; Synaptic Vesicles; Optogenetics; Zebrafish; Synaptic Transmission; Caenorhabditis elegans; Cluster Analysis
PubMed: 36535932
DOI: 10.1038/s41467-022-35324-z -
F1000Research 2019The transient receptor potential vanilloid 1 (TRPV1) is densely expressed in spinal sensory neurons as well as in cranial sensory neurons, including their central... (Review)
Review
The transient receptor potential vanilloid 1 (TRPV1) is densely expressed in spinal sensory neurons as well as in cranial sensory neurons, including their central terminal endings. Recent work in the less familiar cranial sensory neurons, despite their many similarities with spinal sensory neurons, suggest that TRPV1 acts as a calcium channel to release a discrete population of synaptic vesicles. The modular and independent regulation of release offers new questions about nanodomain organization of release and selective actions of G protein-coupled receptors.
Topics: Animals; Excitatory Postsynaptic Potentials; Neurons, Afferent; Signal Transduction; Solitary Nucleus; TRPV Cation Channels
PubMed: 31824648
DOI: 10.12688/f1000research.20795.1 -
Biomolecules Nov 2021Compartmentalization of the membrane is essential for cells to perform highly specific tasks and spatially constrained biochemical functions in topographically defined... (Review)
Review
Compartmentalization of the membrane is essential for cells to perform highly specific tasks and spatially constrained biochemical functions in topographically defined areas. These membrane lateral heterogeneities range from nanoscopic dimensions, often involving only a few molecular constituents, to micron-sized mesoscopic domains resulting from the coalescence of nanodomains. Short-lived domains lasting for a few milliseconds coexist with more stable platforms lasting from minutes to days. This panoply of lateral domains subserves the great variety of demands of cell physiology, particularly high for those implicated in signaling. The dendritic spine, a subcellular structure of neurons at the receiving (postsynaptic) end of central nervous system excitatory synapses, exploits this compartmentalization principle. In its most frequent adult morphology, the mushroom-shaped spine harbors neurotransmitter receptors, enzymes, and scaffolding proteins tightly packed in a volume of a few femtoliters. In addition to constituting a mesoscopic lateral heterogeneity of the dendritic arborization, the dendritic spine postsynaptic membrane is further compartmentalized into spatially delimited nanodomains that execute separate functions in the synapse. This review discusses the functional relevance of compartmentalization and nanodomain organization in synaptic transmission and plasticity and exemplifies the importance of this parcelization in various neurotransmitter signaling systems operating at dendritic spines, using two fast ligand-gated ionotropic receptors, the nicotinic acetylcholine receptor and the glutamatergic receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as paradigmatic examples.
Topics: Dendritic Spines; Neurons; Synapses; Synaptic Transmission
PubMed: 34827695
DOI: 10.3390/biom11111697