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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
Reduction of thalamic and cortical Ih by deletion of TRIP8b produces a mouse model of human absence epilepsy.
Heuermann RJ, Jaramillo TC, Ying SW, Suter BA, Lyman KA, Han Y, Lewis AS, Hampton TG, Shepherd GMG, Goldstein PA, Chetkovich DM
(2016) Neurobiol Dis 85: 81-92
MeSH Terms: Animals, Blotting, Western, Cerebral Cortex, Disease Models, Animal, Electrocardiography, Electrocorticography, Electrodes, Implanted, Epilepsy, Absence, Immunohistochemistry, Male, Membrane Potentials, Membrane Proteins, Mice, Knockout, Motor Activity, Neurons, Patch-Clamp Techniques, Peroxins, Rotarod Performance Test, Sequence Deletion, Thalamus, Tissue Culture Techniques
Show Abstract · Added April 2, 2019
Absence seizures occur in several types of human epilepsy and result from widespread, synchronous feedback between the cortex and thalamus that produces brief episodes of loss of consciousness. Genetic rodent models have been invaluable for investigating the pathophysiological basis of these seizures. Here, we identify tetratricopeptide-containing Rab8b-interacting protein (TRIP8b) knockout mice as a new model of absence epilepsy, featuring spontaneous spike-wave discharges on electroencephalography (EEG) that are the electrographic hallmark of absence seizures. TRIP8b is an auxiliary subunit of the hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which have previously been implicated in the pathogenesis of absence seizures. In contrast to mice lacking the pore-forming HCN channel subunit HCN2, TRIP8b knockout mice exhibited normal cardiac and motor function and a less severe seizure phenotype. Evaluating the circuit that underlies absence seizures, we found that TRIP8b knockout mice had significantly reduced HCN channel expression and function in thalamic-projecting cortical layer 5b neurons and thalamic relay neurons, but preserved function in inhibitory neurons of the reticular thalamic nucleus. Our results expand the known roles of TRIP8b and provide new insight into the region-specific functions of TRIP8b and HCN channels in constraining cortico-thalamo-cortical excitability.
Copyright © 2015 Elsevier Inc. All rights reserved.
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MeSH Terms
"Slow" Voltage-Dependent Inactivation of CaV2.2 Calcium Channels Is Modulated by the PKC Activator Phorbol 12-Myristate 13-Acetate (PMA).
Zhu L, McDavid S, Currie KP
(2015) PLoS One 10: e0134117
MeSH Terms: Animals, Calcium Channel Blockers, Calcium Channels, N-Type, Calcium Signaling, Cattle, Cells, Cultured, Chromaffin Cells, Enzyme Activation, Guanosine Diphosphate, HEK293 Cells, Humans, Kinetics, Patch-Clamp Techniques, Protein Kinase C, Recombinant Proteins, Tetradecanoylphorbol Acetate, Thionucleotides
Show Abstract · Added November 10, 2015
CaV2.2 (N-type) voltage-gated calcium channels (Ca2+ channels) play key roles in neurons and neuroendocrine cells including the control of cellular excitability, neurotransmitter / hormone secretion, and gene expression. Calcium entry is precisely controlled by channel gating properties including multiple forms of inactivation. "Fast" voltage-dependent inactivation is relatively well-characterized and occurs over the tens-to- hundreds of milliseconds timeframe. Superimposed on this is the molecularly distinct, but poorly understood process of "slow" voltage-dependent inactivation, which develops / recovers over seconds-to-minutes. Protein kinases can modulate "slow" inactivation of sodium channels, but little is known about if/how second messengers control "slow" inactivation of Ca2+ channels. We investigated this using recombinant CaV2.2 channels expressed in HEK293 cells and native CaV2 channels endogenously expressed in adrenal chromaffin cells. The PKC activator phorbol 12-myristate 13-acetate (PMA) dramatically prolonged recovery from "slow" inactivation, but an inactive control (4α-PMA) had no effect. This effect of PMA was prevented by calphostin C, which targets the C1-domain on PKC, but only partially reduced by inhibitors that target the catalytic domain of PKC. The subtype of the channel β-subunit altered the kinetics of inactivation but not the magnitude of slowing produced by PMA. Intracellular GDP-β-S reduced the effect of PMA suggesting a role for G proteins in modulating "slow" inactivation. We postulate that the kinetics of recovery from "slow" inactivation could provide a molecular memory of recent cellular activity and help control CaV2 channel availability, electrical excitability, and neurotransmission in the seconds-to-minutes timeframe.
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17 MeSH Terms
Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model.
Ghoshal A, Rook JM, Dickerson JW, Roop GN, Morrison RD, Jalan-Sakrikar N, Lamsal A, Noetzel MJ, Poslusney MS, Wood MR, Melancon BJ, Stauffer SR, Xiang Z, Daniels JS, Niswender CM, Jones CK, Lindsley CW, Conn PJ
(2016) Neuropsychopharmacology 41: 598-610
MeSH Terms: Animals, Antipsychotic Agents, Cognition, Disease Models, Animal, Long-Term Synaptic Depression, Male, Mice, Inbred C57BL, Mice, Knockout, Patch-Clamp Techniques, Phencyclidine, Pyridines, Pyrroles, Receptor, Muscarinic M1, Schizophrenia, Schizophrenic Psychology, Social Behavior
Show Abstract · Added February 18, 2016
Schizophrenia patients exhibit deficits in signaling of the M1 subtype of muscarinic acetylcholine receptor (mAChR) in the prefrontal cortex (PFC) and also display impaired cortical long-term depression (LTD). We report that selective activation of the M1 mAChR subtype induces LTD in PFC and that this response is completely lost after repeated administration of phencyclidine (PCP), a mouse model of schizophrenia. Furthermore, discovery of a novel, systemically active M1 positive allosteric modulator (PAM), VU0453595, allowed us to evaluate the impact of selective potentiation of M1 on induction of LTD and behavioral deficits in PCP-treated mice. Interestingly, VU0453595 fully restored impaired LTD as well as deficits in cognitive function and social interaction in these mice. These results provide critical new insights into synaptic changes that may contribute to behavioral deficits in this mouse model and support a role for selective M1 PAMs as a novel approach for the treatment of schizophrenia.
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4 Members
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16 MeSH Terms
Activation of Metabotropic Glutamate Receptor 7 Is Required for Induction of Long-Term Potentiation at SC-CA1 Synapses in the Hippocampus.
Klar R, Walker AG, Ghose D, Grueter BA, Engers DW, Hopkins CR, Lindsley CW, Xiang Z, Conn PJ, Niswender CM
(2015) J Neurosci 35: 7600-15
MeSH Terms: Animals, CA1 Region, Hippocampal, CA3 Region, Hippocampal, Channelrhodopsins, Electric Stimulation, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Hippocampus, In Vitro Techniques, Inhibitory Postsynaptic Potentials, Interneurons, Long-Term Potentiation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Parvalbumins, Patch-Clamp Techniques, Receptors, Metabotropic Glutamate
Show Abstract · Added February 18, 2016
Of the eight metabotropic glutamate (mGlu) receptor subtypes, only mGlu7 is expressed presynaptically at the Schaffer collateral (SC)-CA1 synapse in the hippocampus in adult animals. Coupled with the inhibitory effects of Group III mGlu receptor agonists on transmission at this synapse, mGlu7 is thought to be the predominant autoreceptor responsible for regulating glutamate release at SC terminals. However, the lack of mGlu7-selective pharmacological tools has hampered direct testing of this hypothesis. We used a novel, selective mGlu7-negative allosteric modulator (NAM), ADX71743, and a newly described Group III mGlu receptor agonist, LSP4-2022, to elucidate the role of mGlu7 in modulating transmission in hippocampal area CA1 in adult C57BL/6J male mice. Interestingly, although mGlu7 agonists inhibit SC-CA1 EPSPs, we found no evidence for activation of mGlu7 by stimulation of SC-CA1 afferents. However, LSP4-2022 also reduced evoked monosynaptic IPSCs in CA1 pyramidal cells and, in contrast to its effect on SC-CA1 EPSPs, ADX71743 reversed the ability of high-frequency stimulation of SC afferents to reduce IPSC amplitudes. Furthermore, blockade of mGlu7 prevented induction of LTP at the SC-CA1 synapse and activation of mGlu7 potentiated submaximal LTP. Together, these data suggest that mGlu7 serves as a heteroreceptor at inhibitory synapses in area CA1 and that the predominant effect of activation of mGlu7 by stimulation of glutamatergic afferents is disinhibition, rather than reduced excitatory transmission. Furthermore, this mGlu7-mediated disinhibition is required for induction of LTP at the SC-CA1 synapse, suggesting that mGlu7 could serve as a novel therapeutic target for treatment of cognitive disorders.
Copyright © 2015 the authors 0270-6474/15/357600-16$15.00/0.
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2 Members
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20 MeSH Terms
Manipulating circadian clock neuron firing rate resets molecular circadian rhythms and behavior.
Jones JR, Tackenberg MC, McMahon DG
(2015) Nat Neurosci 18: 373-5
MeSH Terms: Action Potentials, Animals, Channelrhodopsins, Circadian Rhythm, In Vitro Techniques, Luminescent Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons, Patch-Clamp Techniques, Period Circadian Proteins, Photic Stimulation, Receptors, Dopamine D1, Sodium Channel Blockers, Suprachiasmatic Nucleus, Tetrodotoxin, Time Factors, Vasoactive Intestinal Peptide
Show Abstract · Added March 18, 2020
To examine the interaction between molecular, electrical and behavioral circadian rhythms, we combined optogenetic manipulation of suprachiasmatic nucleus (SCN) firing rate with bioluminescence imaging and locomotor activity monitoring. Manipulating firing rate reset circadian rhythms both ex vivo and in vivo, and this resetting required spikes and network communication. This suggests that SCN firing rate is fundamental to circadian pacemaking as both an input to and output of the molecular clockworks.
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MeSH Terms
Mutational analysis of cysteine residues of the insect odorant co-receptor (Orco) from Drosophila melanogaster reveals differential effects on agonist- and odorant-tuning receptor-dependent activation.
Turner RM, Derryberry SL, Kumar BN, Brittain T, Zwiebel LJ, Newcomb RD, Christie DL
(2014) J Biol Chem 289: 31837-45
MeSH Terms: Allosteric Site, Animals, Biotinylation, Calcium, Cysteine, DNA Mutational Analysis, Drosophila Proteins, Drosophila melanogaster, Epitopes, HEK293 Cells, Humans, Ion Channels, Kinetics, Mutagenesis, Site-Directed, Mutation, Odorants, Patch-Clamp Techniques, Protein Binding, Protein Structure, Tertiary, Receptors, Odorant, Thioglycolates, Triazoles
Show Abstract · Added February 19, 2015
Insect odorant receptors are heteromeric odorant-gated cation channels comprising a conventional odorant-sensitive tuning receptor (ORx) and a highly conserved co-receptor known as Orco. Orco is found only in insects, and very little is known about its structure and the mechanism leading to channel activation. In the absence of an ORx, Orco forms homomeric channels that can be activated by a synthetic agonist, VUAA1. Drosophila melanogaster Orco (DmelOrco) contains eight cysteine amino acid residues, six of which are highly conserved. In this study, we replaced individual cysteine residues with serine or alanine and expressed Orco mutants in Flp-In 293 T-Rex cells. Changes in intracellular Ca(2+) levels were used to determine responses to VUAA1. Replacement of two cysteines (Cys-429 and Cys-449) in a predicted intracellular loop (ICL3), individually or together, gave variants that all showed similar increases in the rate of response and sensitivity to VUAA1 compared with wild-type DmelOrco. Kinetic modeling indicated that the response of the Orco mutants to VUAA1 was faster than wild-type Orco. The enhanced sensitivity and faster response of the Cys mutants was confirmed by whole-cell voltage clamp electrophysiology. In contrast to the results from direct agonist activation of Orco, the two cysteine replacement mutants when co-expressed with a tuning receptor (DmelOR22a) showed an ∼10-fold decrease in potency for activation by 2-methyl hexanoate. Our work has shown that intracellular loop 3 is important for Orco channel activation. Importantly, this study also suggests differences in the structural requirements for the activation of homomeric and heteromeric Orco channel complexes.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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22 MeSH Terms
Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors.
Maltese M, Martella G, Madeo G, Fagiolo I, Tassone A, Ponterio G, Sciamanna G, Burbaud P, Conn PJ, Bonsi P, Pisani A
(2014) Mov Disord 29: 1655-65
MeSH Terms: Animals, Biophysics, Cholinergic Antagonists, Corpus Striatum, Electric Stimulation, Excitatory Postsynaptic Potentials, In Vitro Techniques, Long-Term Potentiation, Mice, Mice, Transgenic, Molecular Chaperones, Mutation, Neurons, Patch-Clamp Techniques, Synapses, Thalamus
Show Abstract · Added February 19, 2015
Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short- and long-term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock-in (Tor1a(+/Δgag) ) mice heterozygous for ΔE-torsinA and their controls (Tor1a(+/+) mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a(+/Δgag) mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short-term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long-term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1 -preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1 -dependent potentiation of N-methyl-d-aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder.
© 2014 International Parkinson and Movement Disorder Society.
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16 MeSH Terms
Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current.
Yang T, Chun YW, Stroud DM, Mosley JD, Knollmann BC, Hong C, Roden DM
(2014) Circulation 130: 224-34
MeSH Terms: 4-Aminopyridine, Action Potentials, Animals, CHO Cells, Cells, Cultured, Cricetinae, Cricetulus, Drug Evaluation, Preclinical, Female, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Models, Animal, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Patch-Clamp Techniques, Phenethylamines, Phosphatidylinositol 3-Kinases, Potassium Channel Blockers, Proto-Oncogene Proteins c-akt, Risk Factors, Signal Transduction, Sulfonamides, Torsades de Pointes, Transfection
Show Abstract · Added June 5, 2014
BACKGROUND - New drugs are routinely screened for IKr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to phosphoinositide 3-kinase inhibitors used in cancer can prolong QT by inhibiting potassium currents and increasing late sodium current (INa-L) in cardiomyocytes. We tested the extent to which IKr blockers with known QT liability generate arrhythmias through this pathway.
METHODS AND RESULTS - Acute exposure to dofetilide, an IKr blocker without other recognized electropharmacologic actions, produced no change in ion currents or action potentials in adult mouse cardiomyocytes, which lack IKr. By contrast, 2 to 48 hours of exposure to the drug generated arrhythmogenic afterdepolarizations and ≥15-fold increases in INa-L. Including phosphatidylinositol 3,4,5-trisphosphate, a downstream effector for the phosphoinositide 3-kinase pathway, in the pipette inhibited these effects. INa-L was also increased, and inhibitable by phosphatidylinositol 3,4,5-trisphosphate, with hours of dofetilide exposure in human-induced pluripotent stem cell-derived cardiomyocytes and in Chinese hamster ovary cells transfected with SCN5A, encoding sodium current. Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased INa-L and afterdepolarizations. Other agents with variable IKr-blocking potencies and arrhythmia liability produced a range of effects on INa-L, from marked increases (E-4031, d-sotalol, thioridazine, and erythromycin) to little or no effect (haloperidol, moxifloxacin, and verapamil).
CONCLUSIONS - Some but not all drugs designated as arrhythmogenic IKr blockers can generate arrhythmias by augmenting INa-L through the phosphoinositide 3-kinase pathway. These data identify a potential mechanism for individual susceptibility to proarrhythmia and highlight the need for a new paradigm to screen drugs for QT prolonging and arrhythmogenic liability.
© 2014 American Heart Association, Inc.
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2 Members
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26 MeSH Terms
GABAA receptor biogenesis is impaired by the γ2 subunit febrile seizure-associated mutation, GABRG2(R177G).
Todd E, Gurba KN, Botzolakis EJ, Stanic AK, Macdonald RL
(2014) Neurobiol Dis 69: 215-24
MeSH Terms: Cell Membrane, Conserved Sequence, Cycloheximide, Endoplasmic Reticulum, Endoplasmic Reticulum-Associated Degradation, Glycosylation, HEK293 Cells, Humans, Models, Molecular, Mutation, Missense, Patch-Clamp Techniques, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Synthesis Inhibitors, Protein Transport, Receptors, GABA-A, Seizures, Febrile, gamma-Aminobutyric Acid
Show Abstract · Added January 24, 2015
A missense mutation in the GABAA receptor γ2L subunit, R177G, was reported in a family with complex febrile seizures (FS). To gain insight into the mechanistic basis for these genetic seizures, we explored how the R177G mutation altered the properties of recombinant α1β2γ2L GABAA receptors expressed in HEK293T cells. Using a combination of electrophysiology, flow cytometry, and immunoblotting, we found that the R177G mutation decreased GABA-evoked whole-cell current amplitudes by decreasing cell surface expression of α1β2γ2L receptors. This loss of receptor surface expression resulted from endoplasmic reticulum (ER) retention of mutant γ2L(R177G) subunits, which unlike wild-type γ2L subunits, were degraded by ER-associated degradation (ERAD). Interestingly, when compared to the condition of homozygous γ2L(R177G) subunit expression, disproportionately low levels of γ2L(R177G) subunits reached the cell surface with heterozygous expression, indicating that wild-type γ2L subunits possessed a competitive advantage over mutant γ2L(R177G) subunits for receptor assembly and/or forward trafficking. Inhibiting protein synthesis with cycloheximide demonstrated that the R177G mutation primarily decreased the stability of an intracellular pool of unassembled γ2L subunits, suggesting that the mutant γ2L(R177G) subunits competed poorly with wild-type γ2L subunits due to impaired subunit folding and/or oligomerization. Molecular modeling confirmed that the R177G mutation could disrupt intrasubunit salt bridges, thereby destabilizing secondary and tertiary structure of γ2L(R177G) subunits. These findings support an emerging body of literature implicating defects in GABAA receptor biogenesis in the pathogenesis of genetic epilepsies (GEs) and FS.
Copyright © 2014. Published by Elsevier Inc.
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18 MeSH Terms