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Excitatory Synaptic Input to Hilar Mossy Cells under Basal and Hyperexcitable Conditions.
Hedrick TP, Nobis WP, Foote KM, Ishii T, Chetkovich DM, Swanson GT
(2017) eNeuro 4:
MeSH Terms: Animals, CA3 Region, Hippocampal, Excitatory Postsynaptic Potentials, Female, Male, Mice, Mice, Inbred C57BL, Mossy Fibers, Hippocampal, Neural Pathways, Neuronal Plasticity, Organ Culture Techniques, Pyramidal Cells, Synapses, Synaptic Transmission
Show Abstract · Added April 2, 2019
Hilar mossy cells (HMCs) in the hippocampus receive glutamatergic input from dentate granule cells (DGCs) via mossy fibers (MFs) and back-projections from CA3 pyramidal neuron collateral axons. Many fundamental features of these excitatory synapses have not been characterized in detail despite their potential relevance to hippocampal cognitive processing and epilepsy-induced adaptations in circuit excitability. In this study, we compared pre- and postsynaptic parameters between MF and CA3 inputs to HMCs in young and adult mice of either sex and determined the relative contributions of the respective excitatory inputs during and models of hippocampal hyperexcitability. The two types of excitatory synapses both exhibited a modest degree of short-term plasticity, with MF inputs to HMCs exhibiting lower paired-pulse (PP) and frequency facilitation than was described previously for MF-CA3 pyramidal cell synapses. MF-HMC synapses exhibited unitary excitatory synaptic currents (EPSCs) of larger amplitude, contained postsynaptic kainate receptors, and had a lower NMDA/AMPA receptor ratio compared to CA3-HMC synapses. Pharmacological induction of hippocampal hyperexcitability transformed the abundant but relatively weak CA3-HMC connections to very large amplitude spontaneous bursts of compound EPSCs (cEPSCs) in young mice (∼P20) and, to a lesser degree, in adult mice (∼P70). CA3-HMC cEPSCs were also observed in slices prepared from mice with spontaneous seizures several weeks after intrahippocampal kainate injection. Strong excitation of HMCs during synchronous CA3 activity represents an avenue of significant excitatory network generation back to DGCs and might be important in generating epileptic networks.
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MeSH Terms
Noise-induced cochlear synaptopathy in rhesus monkeys (Macaca mulatta).
Valero MD, Burton JA, Hauser SN, Hackett TA, Ramachandran R, Liberman MC
(2017) Hear Res 353: 213-223
MeSH Terms: Animals, Auditory Fatigue, Auditory Threshold, Cochlea, Cochlear Diseases, Disease Models, Animal, Evoked Potentials, Auditory, Brain Stem, Hair Cells, Auditory, Hearing, Hearing Loss, Noise-Induced, Macaca mulatta, Noise, Otoacoustic Emissions, Spontaneous, Synapses, Synaptic Transmission, Time Factors
Show Abstract · Added April 3, 2018
Cochlear synaptopathy can result from various insults, including acoustic trauma, aging, ototoxicity, or chronic conductive hearing loss. For example, moderate noise exposure in mice can destroy up to ∼50% of synapses between auditory nerve fibers (ANFs) and inner hair cells (IHCs) without affecting outer hair cells (OHCs) or thresholds, because the synaptopathy occurs first in high-threshold ANFs. However, the fiber loss likely impairs temporal processing and hearing-in-noise, a classic complaint of those with sensorineural hearing loss. Non-human primates appear to be less vulnerable to noise-induced hair-cell loss than rodents, but their susceptibility to synaptopathy has not been studied. Because establishing a non-human primate model may be important in the development of diagnostics and therapeutics, we examined cochlear innervation and the damaging effects of acoustic overexposure in young adult rhesus macaques. Anesthetized animals were exposed bilaterally to narrow-band noise centered at 2 kHz at various sound-pressure levels for 4 h. Cochlear function was assayed for up to 8 weeks following exposure via auditory brainstem responses (ABRs) and otoacoustic emissions (OAEs). A moderate loss of synaptic connections (mean of 12-27% in the basal half of the cochlea) followed temporary threshold shifts (TTS), despite minimal hair-cell loss. A dramatic loss of synapses (mean of 50-75% in the basal half of the cochlea) was seen on IHCs surviving noise exposures that produced permanent threshold shifts (PTS) and widespread hair-cell loss. Higher noise levels were required to produce PTS in macaques compared to rodents, suggesting that primates are less vulnerable to hair-cell loss. However, the phenomenon of noise-induced cochlear synaptopathy in primates is similar to that seen in rodents.
Copyright © 2017 Elsevier B.V. All rights reserved.
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16 MeSH Terms
Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Ca1.2 Ca Channels at Excitatory Synapses.
Wang S, Stanika RI, Wang X, Hagen J, Kennedy MB, Obermair GJ, Colbran RJ, Lee A
(2017) J Neurosci 37: 4679-4691
MeSH Terms: Animals, Calcium Channels, L-Type, Calcium Signaling, Cerebral Cortex, Excitatory Postsynaptic Potentials, Ion Channel Gating, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Protein Transport, Sialoglycoproteins, Signal Transduction, Synapses
Show Abstract · Added April 26, 2017
Voltage-gated Ca1.2 and Ca1.3 (L-type) Ca channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca-dependent facilitation of voltage-gated Ca1.3 Ca channels in transfected cells. Mice lacking densin (densin KO) exhibit defects in synaptic plasticity, spatial memory, and increased anxiety-related behaviors-phenotypes that more closely match those in mice lacking Ca1.2 than Ca1.3. Therefore, we investigated the functional impact of densin on Ca1.2. We report that densin is an essential regulator of Ca1.2 in neurons, but has distinct modulatory effects compared with its regulation of Ca1.3. Densin binds to the N-terminal domain of Ca1.2, but not that of Ca1.3, and increases Ca1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Ca1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Ca1.2 channels, overexpression of densin increases the clustering of Ca1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Ca1.2 in the brain, as well as Ca1.2 current density and signaling to the nucleus, are reduced in neurons from densin KO mice. We conclude that densin is an essential regulator of neuronal Ca1 channels and ensures efficient Ca1.2 Ca signaling at excitatory synapses. The number and localization of voltage-gated Ca Ca channels are crucial determinants of neuronal excitability and synaptic transmission. We report that the protein densin-180 is highly enriched at excitatory synapses in the brain and enhances the cell surface trafficking and postsynaptic localization of Ca1.2 L-type Ca channels in neurons. This interaction promotes coupling of Ca1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Ca1.2 in regulating cognition and mood.
Copyright © 2017 the authors 0270-6474/17/374679-13$15.00/0.
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15 MeSH Terms
Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.
Bluett RJ, Báldi R, Haymer A, Gaulden AD, Hartley ND, Parrish WP, Baechle J, Marcus DJ, Mardam-Bey R, Shonesy BC, Uddin MJ, Marnett LJ, Mackie K, Colbran RJ, Winder DG, Patel S
(2017) Nat Commun 8: 14782
MeSH Terms: Amygdala, Animals, Anxiety, Arachidonic Acids, Behavior, Animal, Benzodioxoles, Disease Susceptibility, Dronabinol, Endocannabinoids, Excitatory Postsynaptic Potentials, Female, Glutamates, Glycerides, Hippocampus, Lipoprotein Lipase, Male, Mice, Inbred ICR, Mice, Knockout, Phenotype, Piperidines, Resilience, Psychological, Signal Transduction, Stress, Psychological, Synapses
Show Abstract · Added April 7, 2017
Stress is a ubiquitous risk factor for the exacerbation and development of affective disorders including major depression and posttraumatic stress disorder. Understanding the neurobiological mechanisms conferring resilience to the adverse consequences of stress could have broad implications for the treatment and prevention of mood and anxiety disorders. We utilize laboratory mice and their innate inter-individual differences in stress-susceptibility to demonstrate a critical role for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) in stress-resilience. Specifically, systemic 2-AG augmentation is associated with a stress-resilient phenotype and enhances resilience in previously susceptible mice, while systemic 2-AG depletion or CB1 receptor blockade increases susceptibility in previously resilient mice. Moreover, stress-resilience is associated with increased phasic 2-AG-mediated synaptic suppression at ventral hippocampal-amygdala glutamatergic synapses and amygdala-specific 2-AG depletion impairs successful adaptation to repeated stress. These data indicate amygdala 2-AG signalling mechanisms promote resilience to adverse effects of acute traumatic stress and facilitate adaptation to repeated stress exposure.
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24 MeSH Terms
Developmental experience-dependent plasticity in the first synapse of the Drosophila olfactory circuit.
Golovin RM, Broadie K
(2016) J Neurophysiol 116: 2730-2738
MeSH Terms: Animals, Animals, Genetically Modified, Arthropod Antennae, Drosophila, Drosophila Proteins, Nerve Net, Olfactory Pathways, Smell, Synapses
Show Abstract · Added March 29, 2017
Evidence accumulating over the past 15 years soundly refutes the dogma that the Drosophila nervous system is hardwired. The preponderance of studies reveals activity-dependent neural circuit refinement driving optimization of behavioral outputs. We describe developmental, sensory input-dependent plasticity in the brain olfactory antennal lobe, which we term long-term central adaption (LTCA). LTCA is evoked by prolonged exposure to an odorant during the first week of posteclosion life, resulting in a persistently decreased response to aversive odors and an enhanced response to attractive odors. This limited window of early-use, experience-dependent plasticity represents a critical period of olfactory circuit refinement tuned by initial sensory input. Consequent behavioral adaptations have been associated with changes in the output of olfactory projection neurons to higher brain centers. Recent studies have indicated a central role for local interneuron signaling in LTCA presentation. Genetic and molecular analyses have implicated the mRNA-binding fragile X mental retardation protein and ataxin-2 regulators, Notch trans-synaptic signaling, and cAMP signal transduction as core regulatory steps driving LTCA. In this article, we discuss the structural, functional, and behavioral changes associated with LTCA and review our current understanding of the molecular pathways underlying these developmental, experience-dependent changes in the olfactory circuitry.
Copyright © 2016 the American Physiological Society.
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9 MeSH Terms
Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models.
Jumbo-Lucioni PP, Parkinson WM, Kopke DL, Broadie K
(2016) Hum Mol Genet 25: 3699-3714
MeSH Terms: Animals, Disease Models, Animal, Drosophila, Drosophila Proteins, Galactokinase, Galactosemias, Glycosylation, Humans, Neuromuscular Junction, Synapses, UTP-Hexose-1-Phosphate Uridylyltransferase, Wnt Signaling Pathway
Show Abstract · Added March 29, 2017
The multiple galactosemia disease states manifest long-term neurological symptoms. Galactosemia I results from loss of galactose-1-phosphate uridyltransferase (GALT), which converts galactose-1-phosphate + UDP-glucose to glucose-1-phosphate + UDP-galactose. Galactosemia II results from loss of galactokinase (GALK), phosphorylating galactose to galactose-1-phosphate. Galactosemia III results from the loss of UDP-galactose 4'-epimerase (GALE), which interconverts UDP-galactose and UDP-glucose, as well as UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. UDP-glucose pyrophosphorylase (UGP) alternatively makes UDP-galactose from uridine triphosphate and galactose-1-phosphate. All four UDP-sugars are essential donors for glycoprotein biosynthesis with critical roles at the developing neuromuscular synapse. Drosophila galactosemia I (dGALT) and II (dGALK) disease models genetically interact; manifesting deficits in coordinated movement, neuromuscular junction (NMJ) development, synaptic glycosylation, and Wnt trans-synaptic signalling. Similarly, dGALE and dUGP mutants display striking locomotor and NMJ formation defects, including expanded synaptic arbours, glycosylation losses, and differential changes in Wnt trans-synaptic signalling. In combination with dGALT loss, both dGALE and dUGP mutants compromise the synaptomatrix glycan environment that regulates Wnt trans-synaptic signalling that drives 1) presynaptic Futsch/MAP1b microtubule dynamics and 2) postsynaptic Frizzled nuclear import (FNI). Taken together, these findings indicate UDP-sugar balance is a key modifier of neurological outcomes in all three interacting galactosemia disease models, suggest that Futsch homolog MAP1B and the Wnt Frizzled receptor may be disease-relevant targets in epimerase and transferase galactosemias, and identify UGP as promising new potential therapeutic target for galactosemia neuropathology.
© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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12 MeSH Terms
Structural basis for integration of GluD receptors within synaptic organizer complexes.
Elegheert J, Kakegawa W, Clay JE, Shanks NF, Behiels E, Matsuda K, Kohda K, Miura E, Rossmann M, Mitakidis N, Motohashi J, Chang VT, Siebold C, Greger IH, Nakagawa T, Yuzaki M, Aricescu AR
(2016) Science 353: 295-9
MeSH Terms: Animals, Ligands, Long-Term Synaptic Depression, Mice, Nerve Tissue Proteins, Neurogenesis, Protein Multimerization, Protein Precursors, Protein Structure, Tertiary, Purkinje Cells, Receptors, Glutamate, Signal Transduction, Synapses
Show Abstract · Added April 6, 2017
Ionotropic glutamate receptor (iGluR) family members are integrated into supramolecular complexes that modulate their location and function at excitatory synapses. However, a lack of structural information beyond isolated receptors or fragments thereof currently limits the mechanistic understanding of physiological iGluR signaling. Here, we report structural and functional analyses of the prototypical molecular bridge linking postsynaptic iGluR δ2 (GluD2) and presynaptic β-neurexin 1 (β-NRX1) via Cbln1, a C1q-like synaptic organizer. We show how Cbln1 hexamers "anchor" GluD2 amino-terminal domain dimers to monomeric β-NRX1. This arrangement promotes synaptogenesis and is essential for D: -serine-dependent GluD2 signaling in vivo, which underlies long-term depression of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses and motor coordination in developing mice. These results lead to a model where protein and small-molecule ligands synergistically control synaptic iGluR function.
Copyright © 2016, American Association for the Advancement of Science.
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13 MeSH Terms
Electrophysiological Measurement of Cannabinoid-Mediated Synaptic Modulation in Acute Mouse Brain Slices.
Báldi R, Ghosh D, Grueter BA, Patel S
(2016) Curr Protoc Neurosci 75: 6.29.1-6.29.19
MeSH Terms: Animals, Brain, Cannabinoid Receptor Modulators, Endocannabinoids, In Vitro Techniques, Mice, Neuronal Plasticity, Patch-Clamp Techniques, Synapses, Synaptic Transmission
Show Abstract · Added March 14, 2018
Endocannabinoids (eCBs) are a class of bioactive lipids that mediate retrograde synaptic modulation at central and peripheral synapses. The highly lipophilic nature of eCBs and the pharmacological tools available to interrogate this system require unique methodological consideration, especially when applied to ex vivo systems such as electrophysiological analysis in acute brain slices. This unit provides protocols for measuring cannabinoid and eCB-mediated synaptic signaling in mouse brain slices, including analysis of short-term, long-term, and tonic eCB signaling modes, and the unique considerations for working with eCBs and TRPV1/cannabinoid ligands in acute brain slices.
Copyright © 2016 John Wiley & Sons, Inc.
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10 MeSH Terms
Synaptic roles for phosphomannomutase type 2 in a new Drosophila congenital disorder of glycosylation disease model.
Parkinson WM, Dookwah M, Dear ML, Gatto CL, Aoki K, Tiemeyer M, Broadie K
(2016) Dis Model Mech 9: 513-27
MeSH Terms: Animals, Congenital Disorders of Glycosylation, Disease Models, Animal, Down-Regulation, Drosophila, Drosophila Proteins, Extracellular Matrix, Glycoproteins, Glycosylation, Longevity, Movement, Neuromuscular Junction, Oligosaccharides, Phosphotransferases (Phosphomutases), Polysaccharides, Posture, Presynaptic Terminals, Signal Transduction, Synapses, Synaptic Transmission
Show Abstract · Added March 29, 2017
Congenital disorders of glycosylation (CDGs) constitute a rapidly growing family of human diseases resulting from heritable mutations in genes driving the production and modification of glycoproteins. The resulting symptomatic hypoglycosylation causes multisystemic defects that include severe neurological impairments, revealing a particularly critical requirement for tightly regulated glycosylation in the nervous system. The most common CDG, CDG-Ia (PMM2-CDG), arises from phosphomannomutase type 2 (PMM2) mutations. Here, we report the generation and characterization of the first Drosophila CDG-Ia model. CRISPR-generated pmm2-null Drosophila mutants display severely disrupted glycosylation and early lethality, whereas RNAi-targeted knockdown of neuronal PMM2 results in a strong shift in the abundance of pauci-mannose glycan, progressive incoordination and later lethality, closely paralleling human CDG-Ia symptoms of shortened lifespan, movement impairments and defective neural development. Analyses of the well-characterized Drosophila neuromuscular junction (NMJ) reveal synaptic glycosylation loss accompanied by defects in both structural architecture and functional neurotransmission. NMJ synaptogenesis is driven by intercellular signals that traverse an extracellular synaptomatrix and are co-regulated by glycosylation and matrix metalloproteinases (MMPs). Specifically, trans-synaptic signaling by the Wnt protein Wingless (Wg) depends on the heparan sulfate proteoglycan (HSPG) co-receptor Dally-like protein (Dlp), which is regulated by synaptic MMP activity. Loss of synaptic MMP2, Wg ligand, Dlp co-receptor and downstream trans-synaptic signaling occurs with PMM2 knockdown. Taken together, this Drosophila CDG disease model provides a new avenue for the dissection of cellular and molecular mechanisms underlying neurological impairments and is a means by which to discover and test novel therapeutic treatment strategies.
© 2016. Published by The Company of Biologists Ltd.
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20 MeSH Terms
Acute and chronic ethanol exposure differentially regulate CB1 receptor function at glutamatergic synapses in the rat basolateral amygdala.
Robinson SL, Alexander NJ, Bluett RJ, Patel S, McCool BA
(2016) Neuropharmacology 108: 474-84
MeSH Terms: Animals, Basolateral Nuclear Complex, Dose-Response Relationship, Drug, Drug Administration Schedule, Ethanol, Excitatory Postsynaptic Potentials, Glutamic Acid, Male, Organ Culture Techniques, Rats, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1, Synapses
Show Abstract · Added March 14, 2018
The endogenous cannabinoid (eCB) system has been suggested to play a key role in ethanol preference and intake, the acute effects of ethanol, and in the development of withdrawal symptoms following ethanol dependence. Ethanol-dependent alterations in glutamatergic signaling within the lateral/basolateral nucleus of the amygdala (BLA) are critical for the development and expression of withdrawal-induced anxiety. Notably, the eCB system significantly regulates both glutamatergic and GABAergic synaptic activity within the BLA. Chronic ethanol exposure significantly alters eCB system expression within regions critical to the expression of emotionality and anxiety-related behavior, including the BLA. Here, we investigated specific interactions between the BLA eCB system and its functional regulation of synaptic activity during acute and chronic ethanol exposure. In tissue from ethanol naïve-rats, a prolonged acute ethanol exposure caused a dose dependent inhibition of glutamatergic synaptic activity via a presynaptic mechanism that was occluded by CB1 antagonist/inverse agonists SR141716a and AM251. Importantly, this acute ethanol inhibition was attenuated following 10 day chronic intermittent ethanol vapor exposure (CIE). CIE exposure also significantly down-regulated CB1-mediated presynaptic inhibition at glutamatergic afferent terminals but spared CB1-inhibition of GABAergic synapses arising from local inhibitory-interneurons. CIE also significantly elevated BLA N-arachidonoylethanolamine (AEA or anandamide) levels and decreased CB1 receptor protein levels. Collectively, these data suggest a dynamic regulation of the BLA eCB system by acute and chronic ethanol.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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13 MeSH Terms