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Transcriptional Control of Synaptic Remodeling through Regulated Expression of an Immunoglobulin Superfamily Protein.
He S, Philbrook A, McWhirter R, Gabel CV, Taub DG, Carter MH, Hanna IM, Francis MM, Miller DM
(2015) Curr Biol 25: 2541-8
MeSH Terms: Acetylcholine, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, GABAergic Neurons, Gene Expression Regulation, Immunoglobulins, Motor Neurons, Nerve Tissue Proteins, Receptors, Cholinergic, Synapses, Transcription Factors
Show Abstract · Added March 26, 2019
Neural circuits are actively remodeled during brain development, but the molecular mechanisms that trigger circuit refinement are poorly understood. Here, we describe a transcriptional program in C. elegans that regulates expression of an Ig domain protein, OIG-1, to control the timing of synaptic remodeling. DD GABAergic neurons reverse polarity during larval development by exchanging the locations of pre- and postsynaptic components. In newly born larvae, DDs receive cholinergic inputs in the dorsal nerve cord. These inputs are switched to the ventral side by the end of the first larval (L1) stage. VD class GABAergic neurons are generated in the late L1 and are postsynaptic to cholinergic neurons in the dorsal nerve cord but do not remodel. We investigated remodeling of the postsynaptic apparatus in DD and VD neurons using targeted expression of the acetylcholine receptor (AChR) subunit, ACR-12::GFP. We determined that OIG-1 antagonizes the relocation of ACR-12 from the dorsal side in L1 DD neurons. During the L1/L2 transition, OIG-1 is downregulated in DD neurons by the transcription factor IRX-1/Iroquois, allowing the repositioning of synaptic inputs to the ventral side. In VD class neurons, which normally do not remodel, the transcription factor UNC-55/COUP-TF turns off IRX-1, thus maintaining high levels of OIG-1 to block the removal of dorsally located ACR-12 receptors. OIG-1 is secreted from GABA neurons, but its anti-plasticity function is cell autonomous and may not require secretion. Our study provides a novel mechanism by which synaptic remodeling is set in motion through regulated expression of an Ig domain protein.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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Cholinergic capacity mediates prefrontal engagement during challenges to attention: evidence from imaging genetics.
Berry AS, Blakely RD, Sarter M, Lustig C
(2015) Neuroimage 108: 386-95
MeSH Terms: Adult, Attention, Cholinergic Fibers, Diagnostic Imaging, Female, Humans, Magnetic Resonance Imaging, Male, Membrane Transport Proteins, Multivariate Analysis, Prefrontal Cortex, Receptors, Cholinergic, Symporters
Show Abstract · Added February 12, 2015
In rodent studies, elevated cholinergic neurotransmission in right prefrontal cortex (PFC) is essential for maintaining attentional performance, especially in challenging conditions. Apparently paralleling the rises in acetylcholine seen in rodent studies, fMRI studies in humans reveal right PFC activation at or near Brodmann's areas 9 (BA 9) increases in response to elevated attentional demand. In the present study, we leveraged human genetic variability in the cholinergic system to test the hypothesis that the cholinergic system contributes to the BA 9 response to attentional demand. Specifically, we scanned (BOLD fMRI) participants with a polymorphism of the choline transporter gene that is thought to limit choline transport capacity (Ile89Val variant of the choline transporter gene SLC5A7, rs1013940) and matched controls while they completed a task previously used to demonstrate demand-related increases in right PFC cholinergic transmission in rats and right PFC activation in humans. As hypothesized, we found that although controls showed the typical pattern of robust BA 9 responses to increased attentional demand, Ile89Val participants did not. Further, pattern analysis of activation within this region significantly predicted participant genotype. Additional exploratory pattern classification analyses suggested that Ile89Val participants differentially recruited orbitofrontal cortex and parahippocampal gyrus to maintain attentional performance to the level of controls. These results contribute to a growing body of translational research clarifying the role of cholinergic signaling in human attention and functional neural measures, and begin to outline the risk and resiliency factors associated with potentially suboptimal cholinergic function with implications for disorders characterized by cholinergic dysregulation.
Copyright © 2015 Elsevier Inc. All rights reserved.
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13 MeSH Terms
C. elegans dopaminergic D2-like receptors delimit recurrent cholinergic-mediated motor programs during a goal-oriented behavior.
Correa P, LeBoeuf B, García LR
(2012) PLoS Genet 8: e1003015
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cholinergic Antagonists, Cholinergic Neurons, Copulation, Disorders of Sex Development, Dopamine, Female, Male, Muscle Contraction, Receptors, Cholinergic, Receptors, Dopamine D2, Sexual Behavior, Animal, Signal Transduction, Vulva
Show Abstract · Added September 3, 2013
Caenorhabditis elegans male copulation requires coordinated temporal-spatial execution of different motor outputs. During mating, a cloacal circuit consisting of cholinergic sensory-motor neurons and sex muscles maintains the male's position and executes copulatory spicule thrusts at his mate's vulva. However, distinct signaling mechanisms that delimit these behaviors to their proper context are unclear. We found that dopamine (DA) signaling directs copulatory spicule insertion attempts to the hermaphrodite vulva by dampening spurious stimulus-independent sex muscle contractions. From pharmacology and genetic analyses, DA antagonizes stimulatory ACh signaling via the D2-like receptors, DOP-2 and DOP-3, and Gα(o/i) proteins, GOA-1 and GPA-7. Calcium imaging and optogenetics suggest that heightened DA-expressing ray neuron activities coincide with the cholinergic cloacal ganglia function during spicule insertion attempts. D2-like receptor signaling also attenuates the excitability of additional mating circuits to reduce the duration of mating attempts with unproductive and/or inappropriate partners. This suggests that, during wild-type mating, simultaneous DA-ACh signaling modulates the activity threshold of repetitive motor programs, thus confining the behavior to the proper situational context.
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16 MeSH Terms
The cholinergic hypothesis of cognitive aging revisited again: cholinergic functional compensation.
Dumas JA, Newhouse PA
(2011) Pharmacol Biochem Behav 99: 254-61
MeSH Terms: Acetylcholine, Aging, Alzheimer Disease, Cognition, Cognition Disorders, Humans, Models, Neurological, Models, Psychological, Nootropic Agents, Receptors, Cholinergic
Show Abstract · Added March 3, 2020
It is now possible to reevaluate the cholinergic hypothesis of age-related cognitive dysfunction based on a synthesis of new evidence from cholinergic stimulation studies and cognitive models. We propose that a change of functional circuitry that can be observed through a combination of pharmacologic challenge and functional neuroimaging is associated with age-related changes in cholinergic system functioning. Psychopharmacological manipulations using cholinergic agonists and antagonists have been consistent in replicating patterns of aging seen in functional imaging studies. In addition, studies of anticholinesterase drugs in patients with Alzheimer's disease and mild cognitive impairment show support for the proposal that cholinergic compensation causes alterations in task-related brain activity. Thus, the cholinergic hypothesis of age-related cognitive dysfunction deserves further consideration as new methodologies for evaluating its validity are increasingly being used. Future directions for testing hypotheses generated from this model are presented.
Copyright © 2011 Elsevier Inc. All rights reserved.
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Summary of the National Institute on Aging-sponsored conference on depressive symptoms and cognitive complaints in the menopausal transition.
Maki PM, Freeman EW, Greendale GA, Henderson VW, Newhouse PA, Schmidt PJ, Scott NF, Shively CA, Soares CN
(2010) Menopause 17: 815-22
MeSH Terms: Aging, Animals, Cardiovascular Diseases, Clinical Trials as Topic, Cognition Disorders, Congresses as Topic, Depression, Estrogens, Female, Hormone Replacement Therapy, Humans, Menopause, National Institute on Aging (U.S.), Neurons, Receptors, Cholinergic, Risk, Risk Factors, United States
Show Abstract · Added March 3, 2020
OBJECTIVE - The National Institutes of Health and The North American Menopause Society sponsored a symposium to understand the impact of the menopausal transition on mood symptoms and cognitive disorders and to identify research priorities for further investigation.
METHODS - The symposium was divided into a morning session on depressive symptoms and an afternoon session on cognitive function. There were four speakers per session, and each session covered four methodological approaches, including longitudinal cohort studies, randomized intervention trials, pharmacological challenge studies, and clinical diagnosis. Interactive panel discussions focused on translating research findings to clinical practice.
RESULTS - Most women do not experience serious depressive symptoms during the menopausal transition, but a subgroup of women is at increased risk. Slight changes in memory function and processing speed are evident during the menopausal transition, and physiological factors associated with hot flashes may contribute to memory problems. Clinical trial evidence indicates that estradiol therapy can be effective in treating perimenopausal depression. There is some limited evidence of a cognitive benefit with estrogen-alone therapy in younger postmenopausal women and stronger evidence that certain forms of combination hormone therapy produce modest deficits in verbal memory in younger postmenopausal women.
CONCLUSIONS - Routine evaluation of depressive symptoms in perimenopausal women is warranted by the literature. Quick and valid screening tools for assessing depression in the clinic are available online and free of charge. Identifying a cognitively neutral or beneficial combination therapy for the treatment of menopausal symptoms in naturally postmenopausal women is an important goal for future research.
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Group I mGluRs and long-term depression: potential roles in addiction?
Grueter BA, McElligott ZA, Winder DG
(2007) Mol Neurobiol 36: 232-44
MeSH Terms: Animals, Depressive Disorder, Genetic Linkage, Hippocampus, Humans, Long-Term Synaptic Depression, Memory, Neuronal Plasticity, Receptors, Adrenergic, Receptors, Cholinergic, Receptors, Metabotropic Glutamate, Signal Transduction, Substance-Related Disorders
Show Abstract · Added May 19, 2014
Addiction is an enormous societal problem. A number of recent studies have focused on adaptations at glutamatergic synapses that may play a role in the behavioral responses to drugs of abuse. These studies have largely focused on NMDA receptor-dependent forms of synaptic plasticity such as NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD). A growing body of evidence, however, suggests that metabotropic glutamate receptors (mGluRs) also play important roles in the behavioral responses to drugs of abuse and participate in producing synaptic plasticity at glutamate synapses. In this review, we focus first on the evidence supporting a role for mGluRs in addiction and then on the properties of mGluR-dependent forms of synaptic plasticity, focusing in particular on Gq-linked receptor-induced LTD.
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13 MeSH Terms
Involvement of p120 catenin in myopodial assembly and nerve-muscle synapse formation.
Madhavan R, Zhao XT, Reynolds AB, Peng HB
(2006) J Neurobiol 66: 1511-27
MeSH Terms: Agrin, Animals, Blotting, Western, Catenins, Cell Adhesion Molecules, Cells, Cultured, Coculture Techniques, Embryo, Nonmammalian, Gene Expression, Gene Expression Regulation, Green Fluorescent Proteins, Humans, Muscle Cells, Neuromuscular Junction, Neurons, Phosphoproteins, Pseudopodia, Receptors, Cholinergic, Time Factors, Tyrosine, Xenopus
Show Abstract · Added March 5, 2014
At developing neuromuscular junctions (NMJs), muscles initially contact motor axons by microprocesses, or myopodia, which are induced by nerves and nerve-secreted agrin, but it is unclear how myopodia are assembled and how they influence synaptic differentiation at the NMJ. Here, we report that treatment of cultured muscle cells with agrin transiently depleted p120 catenin (p120ctn) from cadherin junctions in situ, and increased the tyrosine phosphorylation and decreased the cadherin-association of p120ctn in cell extracts. Whereas ectopic expression of wild-type p120ctn in muscle generated myopodia in the absence of agrin, expression of a specific dominant-negative mutant form of p120ctn, which blocks filopodial assembly in nonmuscle cells, suppressed nerve- and agrin-induction of myopodia. Significantly, approaching neurites triggered reduced acetylcholine receptor (AChR) clustering along the edges of muscle cells expressing mutant p120ctn than of control cells, although the ability of the mutant cells to cluster AChRs was itself normal. Our results indicate a novel role of p120ctn in agrin-induced myopodial assembly and suggest that myopodia increase muscle-nerve contacts and muscle's access to neural agrin to promote NMJ formation.
Copyright 2006 Wiley Periodicals, Inc.
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21 MeSH Terms
Structural alterations at the neuromuscular junctions of matrix metalloproteinase 3 null mutant mice.
VanSaun M, Herrera AA, Werle MJ
(2003) J Neurocytol 32: 1129-42
MeSH Terms: Agrin, Animals, Cell Differentiation, Excitatory Postsynaptic Potentials, Fluorescent Antibody Technique, Matrix Metalloproteinase 3, Mice, Mice, Knockout, Microscopy, Electron, Neuromuscular Junction, Reaction Time, Receptors, Cholinergic, Synaptic Membranes, Synaptic Transmission, Up-Regulation
Show Abstract · Added May 13, 2014
Matrix metalloproteinases are important regulators of extracellular matrix molecules and cell-cell signaling. Antibodies to matrix metalloproteinase 3 (MMP3) recognize molecules at the frog neuromuscular junction, and MMP3 can remove agrin from synaptic basal lamina (VanSaun & Werle, 2000). To gain insight into the possible roles of MMP3 at the neuromuscular junction, detailed observations were made on the structure and function of the neuromuscular junctions in MMP3 null mutant mice. Striking differences were found in the appearance of the postsynaptic apparatus of MMP3 null mutant mice. Endplates had an increased volume of AChR stained regions within the endplate structure, leaving only small regions devoid of AChRs. Individual postsynaptic gutters were wider, containing prominent lines that represent the AChRs concentrated at the tops of the junctional folds. Electron microscopy revealed a dramatic increase in the number and size of the junctional folds, in addition to ectopically located junctional folds. Electrophysiological recordings revealed no change in quantal content or MEPP frequency, but there was an increase in MEPP rise time in a subset of endplates. No differences were observed in the rate or extent of developmental synapse elimination. In vitro cleavage experiments revealed that MMP3 directly cleaves agrin. Increased agrin immunofluorescence was observed at the neuromuscular junctions of MMP3 null mutant mice. These results provide strong evidence that MMP3 is involved in the control of synaptic structure at the neuromuscular junction and they support the hypothesis that MMP3 is involved in the regulation of agrin at the neuromuscular junction.
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15 MeSH Terms
Role of Cl- co-transporters in the excitation produced by GABAA receptors in juvenile bovine adrenal chromaffin cells.
Xie Z, Currie KP, Cahill AL, Fox AP
(2003) J Neurophysiol 90: 3828-37
MeSH Terms: Adrenal Glands, Animals, Bicuculline, Calcium, Calcium Channels, Catecholamines, Cats, Cattle, Cells, Cultured, Chromaffin Cells, Electrophysiology, GABA Agonists, GABA Antagonists, Intracellular Fluid, Lanthanum, Membrane Potentials, Muscimol, Patch-Clamp Techniques, Receptors, Cholinergic, Receptors, GABA-A, Symporters
Show Abstract · Added March 30, 2013
GABA is the primary inhibitory neurotransmitter in the adult mammalian brain. However, in neonatal animals, activation of Cl(-)-permeable GABA receptors is excitatory and appears to depend on the expression of a Na(+)-K(+)-2Cl- cotransporter (NKCC) that elevates intracellular Cl- levels, leading to a depolarized Cl- equilibrium potential (ECl). The change from excitation to inhibition appears to involve the expression of the K+/Cl- co-transporter, KCC2, which lowers intracellular Cl- levels resulting in a hyperpolarized ECl. In this study, we show that bovine chromaffin cells from 4- to 5-mo-old animals are excited by GABA. Activation of GABAA receptors depolarizes the cells, opens voltage-dependent Ca2+ channels, elevates [Ca2+]i, and promotes the release of catecholamines. Blockade of voltage-dependent Ca2+ channels prevents the elevation of [Ca2+]i by GABA. The extrapolated anion reversal potential in these cells is approximately -28 mV, indicating a resting intracellular anion concentration of approximately 50 mM. Expression of KCC2 protein was not detected in the juvenile chromaffin cells. In contrast, clear expression of NKCC1 was observed. Blockade of NKCC1 should reduce the intracellular Cl- concentration and hyperpolarize ECl. Bumetanide, an NKCC1 blocker, reduced the elevation of [Ca2+]i by GABA. In some cells, activation of GABAA receptors inhibits responses to excitatory neurotransmitters, even though GABA itself is depolarizing. Co-activation of cholinergic and GABAA receptors in chromaffin cells produced elevations in [Ca2+]i that were comparable to those produced by cholinergic receptors alone. Our data showing the selective expression of chloride co-transporters and the resulting strongly depolarized anion reversal potential may help explain how activation of GABAA receptors causes sufficient excitation to elicit catecholamine release from chromaffin cells.
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21 MeSH Terms
Different intracellular localization of inositol 1,4,5-trisphosphate and ryanodine receptors in cardiomyocytes.
Kijima Y, Saito A, Jetton TL, Magnuson MA, Fleischer S
(1993) J Biol Chem 268: 3499-506
MeSH Terms: Animals, Blotting, Western, Calcium Channels, Cells, Cultured, Dogs, Heart Ventricles, Immunohistochemistry, Inositol 1,4,5-Trisphosphate, Inositol 1,4,5-Trisphosphate Receptors, Male, Microscopy, Immunoelectron, Molecular Weight, Myocardium, Rats, Rats, Sprague-Dawley, Receptors, Cell Surface, Receptors, Cholinergic, Receptors, Cytoplasmic and Nuclear, Ryanodine, Ryanodine Receptor Calcium Release Channel, Subcellular Fractions
Show Abstract · Added February 23, 2011
The ryanodine and inositol 1,4,5-trisphosphate (IP3) receptors have previously been found to be intracellular Ca2+ release channels characterized by their large size and 4-fold symmetry. In this study, cardiomyocytes are found to have a different intracellular localization for the two receptors. At the level of light microscopy, the IP3 receptor is immunolocalized in rat ventricular cardiomyocytes at the region of the intercalated discs. By contrast, immunoreactivity of the ryanodine receptor is observed as transverse bands throughout the length of the cardiomyocyte, coincident with the triad junction at the I-bands. At the level of electron microscopy, immunogold particles directed to the IP3 receptor specifically decorate the intercalated discs of rat ventricular and atrial cardiomyocytes, preferentially at the fascia adherens. Binding of [3H] IP3 and [3H]ryanodine were measured in cardiac subcellular fractions. IP3 binding is enriched in a fraction containing intercalated discs. Little or no IP3 binding was detected in longitudinal sarcoplasmic reticulum (SR), junctional SR, sarcolemma, mitochondria, and submitochondrial vesicles. Ryanodine binding is the highest in junctional SR. We conclude that the IP3 receptor is present in ventricular and atrial cardiomyocytes and localized at the region of the intercalated discs. These results suggest a possible role of the IP3 receptor in Ca2+ entry through intercalated discs and/or intercellular signaling between cardiomyocytes.
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21 MeSH Terms