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Neurobiology of Disease Jan 2022This review provides an overview of the synaptic dysfunction of neuronal circuits and the ensuing behavioral alterations caused by mutations in autism spectrum disorder... (Review)
Review
This review provides an overview of the synaptic dysfunction of neuronal circuits and the ensuing behavioral alterations caused by mutations in autism spectrum disorder (ASD)-linked genes directly or indirectly affecting the postsynaptic neuronal compartment. There are plenty of ASD risk genes, that may be broadly grouped into those involved in gene expression regulation (epigenetic regulation and transcription) and genes regulating synaptic activity (neural communication and neurotransmission). Notably, the effects mediated by ASD-associated genes can vary extensively depending on the developmental time and/or subcellular site of expression. Therefore, in order to gain a better understanding of the mechanisms of disruptions in postsynaptic function, an effort to better model ASD in experimental animals is required to improve standardization and increase reproducibility within and among studies. Such an effort holds promise to provide deeper insight into the development of these disorders and to improve the translational value of preclinical studies.
Topics: Animals; Autism Spectrum Disorder; Epigenesis, Genetic; Neurons; Reproducibility of Results; Synaptic Transmission
PubMed: 34838666
DOI: 10.1016/j.nbd.2021.105564 -
British Journal of Pharmacology Feb 2021
Topics: Neurons; Synaptic Transmission
PubMed: 33534917
DOI: 10.1111/bph.15354 -
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 -
Neurobiology of Learning and Memory Dec 2019Persistent changes that occur in brain circuits are classically thought to be mediated by long-term modifications in synaptic efficacy. Yet, many studies have shown that... (Review)
Review
Persistent changes that occur in brain circuits are classically thought to be mediated by long-term modifications in synaptic efficacy. Yet, many studies have shown that voltage-gated ion channels located at the input and output side of the neurons are also the subject to persistent modifications. These channels are thus responsible for intrinsic plasticity that is expressed in many different neuronal types including glutamatergic principal neurons and GABAergic interneurons. As for synaptic plasticity, activation of synaptic glutamate receptors initiate persistent modification in neuronal excitability. We review here how synaptic input can be efficiently altered by activity-dependent modulation of ion channels that control EPSP amplification, spike threshold or resting membrane potential. We discuss the nature of the learning rules shared by intrinsic and synaptic plasticity, the mechanisms of ion channel regulation and the impact of intrinsic plasticity on induction of synaptic modifications.
Topics: Action Potentials; Animals; Brain; Ion Channels; Learning; Memory; Neuronal Plasticity; Neurons; Synaptic Transmission
PubMed: 31539624
DOI: 10.1016/j.nlm.2019.107095 -
Molecular and Cellular Neurosciences Jul 2022A harmonized interplay between the central nervous system and the five peripheral end organs is how the vestibular system helps organisms feel a sense of balance and... (Review)
Review
A harmonized interplay between the central nervous system and the five peripheral end organs is how the vestibular system helps organisms feel a sense of balance and motion in three-dimensional space. The receptor cells of this system, much like their cochlear equivalents, are the specialized hair cells. However, research over the years has shown that the vestibular end organs and hair cells evolved very differently from their cochlear counterparts. The structurally unique calyceal synapse, which appeared much later in the evolutionary time scale, and continues to intrigue researchers, is now known to support several forms of synaptic neurotransmission. The conventional quantal transmission is believed to employ the ribbon structures, which carry several tethered vesicles filled with neurotransmitters. However, the field of vestibular hair cell synaptic molecular anatomy is still at a nascent stage and needs further work. In this review, we will touch upon the basic structure and function of the peripheral vestibular system, with the focus on the various modes of neurotransmission at the type I vestibular hair cells. We will also shed light on the current knowledge about the molecular anatomy of the vestibular hair cell synapses and vestibular synaptopathy.
Topics: Cochlea; Hair Cells, Vestibular; Neurotransmitter Agents; Synapses; Synaptic Transmission
PubMed: 35667549
DOI: 10.1016/j.mcn.2022.103749 -
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 -
Current Opinion in Neurobiology Oct 2022Sustained neurotransmission is driven by a continuous supply of synaptic vesicles to the release sites and modulated by synaptic vesicle dynamics. However, synaptic... (Review)
Review
Sustained neurotransmission is driven by a continuous supply of synaptic vesicles to the release sites and modulated by synaptic vesicle dynamics. However, synaptic vesicle dynamics in synapses remain elusive because of technical limitations. Recent advances in fluorescence imaging techniques have enabled the tracking of single synaptic vesicles in small central synapses in living neurons. Single vesicle tracking has uncovered a wealth of new information about synaptic vesicle dynamics both within and outside presynaptic terminals, showing that single vesicle tracking is an effective tool for studying synaptic vesicle dynamics. Particularly, single vesicle tracking with high spatiotemporal resolution has revealed the dependence of synaptic vesicle dynamics on the location, stages of recycling, and neuronal activity. This review summarizes the recent findings from single synaptic vesicle tracking in small central synapses and their implications in synaptic transmission and pathogenic mechanisms of neurodegenerative diseases.
Topics: Neurons; Presynaptic Terminals; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 35803103
DOI: 10.1016/j.conb.2022.102596 -
International Journal of Molecular... Jul 2023Dopamine (DA) inhibits excitatory synaptic transmission in the anterior cingulate cortex (ACC), a brain region involved in the sensory and affective processing of pain....
Dopamine (DA) inhibits excitatory synaptic transmission in the anterior cingulate cortex (ACC), a brain region involved in the sensory and affective processing of pain. However, the DA modulation of inhibitory synaptic transmission in the ACC and its alteration of the excitatory/inhibitory (E/I) balance remains relatively understudied. Using patch-clamp recordings, we demonstrate that neither DA applied directly to the tissue slice nor complete Freund's adjuvant (CFA) injected into the hind paw significantly impacted excitatory currents (eEPSCs) in the ACC, when recorded without pharmacological isolation. However, individual neurons exhibited varied responses to DA, with some showing inhibition, potentiation, or no response. The degree of eEPSC inhibition by DA was higher in naïve slices compared to that in the CFA condition. The baseline inhibitory currents (eIPSCs) were greater in the CFA-treated slices, and DA specifically inhibited eIPSCs in the CFA-treated, but not naïve group. DA and CFA treatment did not alter the balance between excitatory and inhibitory currents. Spontaneous synaptic activity revealed that DA reduced the frequency of the excitatory currents in CFA-treated mice and decreased the amplitude of the inhibitory currents, specifically in CFA-treated mice. However, the overall synaptic drive remained similar between the naïve and CFA-treated mice. Additionally, GABAergic currents were pharmacologically isolated and found to be robustly inhibited by DA through postsynaptic D2 receptors and G-protein activity. Overall, the study suggests that CFA-induced inflammation and DA do not significantly affect the balance between excitatory and inhibitory currents in ACC neurons, but activity-dependent changes may be observed in the DA modulation of presynaptic glutamate release in the presence of inflammation.
Topics: Mice; Animals; Dopamine; Gyrus Cinguli; Synaptic Transmission; Pain; Glutamic Acid; Inflammation
PubMed: 37446289
DOI: 10.3390/ijms241311113 -
Biochimica Et Biophysica Acta.... Nov 2022Adequate homeostasis of lipid, protein and carbohydrate metabolism is essential for cells to perform highly specific tasks in our organism, and the brain, with its... (Review)
Review
Adequate homeostasis of lipid, protein and carbohydrate metabolism is essential for cells to perform highly specific tasks in our organism, and the brain, with its uniquely high energetic requirements, posesses singular characteristics. Some of these are related to its extraordinary dotation of synapses, the specialized subcelluar structures where signal transmission between neurons occurs in the central nervous system. The post-synaptic compartment of excitatory synapses, the dendritic spine, harbors key molecules involved in neurotransmission tightly packed within a minute volume of a few femtoliters. The spine is further compartmentalized into nanodomains that facilitate the execution of temporo-spatially separate functions in the synapse. Lipids play important roles in this structural and functional compartmentalization and in mechanisms that impact on synaptic transmission. This review analyzes the structural and dynamic processes involving lipids at the synapse, highlighting the importance of their homeostatic balance for the physiology of this complex and highly specialized structure, and underscoring the pathologies associated with disbalances of lipid metabolism, particularly in the perinatal and late adulthood periods of life. Although small variations of the lipid profile in the brain take place throughout the adult lifespan, the pathophysiological consequences are clinically manifested mostly during late adulthood. Disturbances in lipid homeostasis in the perinatal period leads to alterations during nervous system development, while in late adulthood they favor the occurrence of neurodegenerative diseases.
Topics: Lipidomics; Lipids; Neurons; Synapses; Synaptic Transmission
PubMed: 35964712
DOI: 10.1016/j.bbamem.2022.184033 -
Vitamins and Hormones 2020The mammalian brain contains many regions which synthesize and release the hormone and transmitter corticotropin releasing factor. This peptide is a key player in the... (Review)
Review
The mammalian brain contains many regions which synthesize and release the hormone and transmitter corticotropin releasing factor. This peptide is a key player in the function of the hypothalamic-pituitary-adrenal axis and has major role in mediating the endocrine limb of the stress response. However, there are several regions outside of the paraventricular nucleus of the hypothalamus which synthesize this peptide in which it has a role more akin to a classical neurotransmitter. A significant body of literature exists in which its role as a transmitter and its cellular effects in many brain regions, as well as how it affects various forms of behavior, is described. However, the receptors which corticotropin releasing factor interacts with in the brain are G-protein coupled receptors, and therefore their activation promotes a multitude of cellular effects. Despite this, comparatively little research has been done to investigate how this peptide affects excitatory synaptic transmission in the brain. This is important because both excitatory and inhibitory regulation of physiology are important extrinsic factors in the operation of neurons which occur in conjunction with their intrinsic properties. By not taking into account how corticotropin releasing factor affects these processes, a complete picture of this peptide's role in brain function is not available. In this chapter, the limited body of research which has explicitly investigated how corticotropin releasing factor affects excitatory synaptic transmission in various brain regions will be explored.
Topics: Animals; Brain; Corticotropin-Releasing Hormone; Mammals; Stress, Physiological; Synaptic Transmission
PubMed: 32723550
DOI: 10.1016/bs.vh.2020.04.003