GABAergic activation of an inwardly rectifying K<sup>+</sup> current in mouse cerebellar Purkinje cells

Tabata, Toshihide; Haruki, Shigeki; Nakayama, Haruo; Kano, Masanobu

doi:10.1113/jphysiol.2004.081000

Cited by 31 publications

(33 citation statements)

References 56 publications

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“…Chlorzoxazone is a known activator of calcium‐activated potassium (K Ca ) channels, both BK and the related small‐conductance calcium‐activated potassium (SK) channel 36, 41, 42, 43. Baclofen, a GABA B agonist, potentiates a subthreshold‐activated potassium channel current in Purkinje neurons likely mediated by G‐protein‐coupled inwardly rectifying potassium (GIRK) channels 44. In order to confirm whether K Ca channels are a target for restored spiking in ATXN1[82Q] Purkinje neurons, we tested other known activators of K Ca channels in the presence of baclofen to determine their ability to restore spiking.…”

Section: Resultsmentioning

confidence: 99%

Targeting potassium channels to treat cerebellar ataxia

Bushart

Chopra

Singh

et al. 2018

Ann Clin Transl Neurol

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ObjectivePurkinje neuron dysfunction is associated with cerebellar ataxia. In a mouse model of spinocerebellar ataxia type 1 (SCA1), reduced potassium channel function contributes to altered membrane excitability resulting in impaired Purkinje neuron spiking. We sought to determine the relationship between altered membrane excitability and motor dysfunction in SCA1 mice.MethodsPatch‐clamp recordings in acute cerebellar slices and motor phenotype testing were used to identify pharmacologic agents which improve Purkinje neuron physiology and motor performance in SCA1 mice. Additionally, we retrospectively reviewed records of patients with SCA1 and other autosomal‐dominant SCAs with prominent Purkinje neuron involvement to determine whether currently approved potassium channel activators were tolerated.ResultsActivating calcium‐activated and subthreshold‐activated potassium channels improved Purkinje neuron spiking impairment in SCA1 mice (P < 0.05). Additionally, dendritic hyperexcitability was improved by activating subthreshold‐activated potassium channels but not calcium‐activated potassium channels (P < 0.01). Improving spiking and dendritic hyperexcitability through a combination of chlorzoxazone and baclofen produced sustained improvements in motor dysfunction in SCA1 mice (P < 0.01). Retrospective review of SCA patient records suggests that co‐treatment with chlorzoxazone and baclofen is tolerated.InterpretationTargeting both altered spiking and dendritic membrane excitability is associated with sustained improvements in motor performance in SCA1 mice, while targeting altered spiking alone produces only short‐term improvements in motor dysfunction. Potassium channel activators currently in clinical use are well tolerated and may provide benefit in SCA patients. Future clinical trials with potassium channel activators are warranted in cerebellar ataxia.

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Section: Resultsmentioning

confidence: 99%

Targeting potassium channels to treat cerebellar ataxia

Bushart

Chopra

Singh

et al. 2018

Ann Clin Transl Neurol

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“…To test the involvement of G i/o protein, the primary messenger coupled to GABA B R, we assessed LTD glu in Purkinje cells pretreated with pertussis toxin (PTX), a G i/o protein inhibitor (500 ng ml −1 , > 16 h). This pretreatment is reported to eliminate a G i/o protein‐coupled inwardly rectifying K + current in Purkinje cells (Tabata et al 2005). In the normal saline, the conjunctive stimuli induced LTD glu in the PTX‐pretreated cells while the magnitude of LTD glu (peak amplitude at 48–52 min after the conjunctive stimuli, 90.1 ± 4.6%, n = 5) was small compared with that in the untreated cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Postsynaptic GABA_B receptor signalling enhances LTD in mouse cerebellar Purkinje cells

Kamikubo

Tabata

Kakizawa

et al. 2007

The Journal of Physiology

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Long-term depression (LTD) of excitatory transmission at cerebellar parallel fibre-Purkinje cell synapses is a form of synaptic plasticity crucial for cerebellar motor learning. Around the postsynaptic membrane of these synapses, B-type γ-aminobutyric acid receptor (GABA B R), a G i/o protein-coupled receptor for the inhibitory transmitter GABA is concentrated and closely associated with type-1 metabotropic glutamate receptors (mGluR1) whose signalling is a key factor for inducing LTD. We found that in cultured Purkinje cells, GABA B R activation enhanced LTD of a glutamate-evoked current (LTD glu ), increasing the magnitude of depression. It has been reported that parallel fibre-Purkinje cell synapses receive a micromolar level of GABA spilt over from the synaptic terminals of the neighbouring GABAergic interneurons. This level of GABA was able to enhance LTD glu . Our pharmacological analyses revealed that the βγ subunits but not the α subunit of G i/o protein mediated GABA B R-mediated LTD glu enhancement. G i/o protein activation was sufficient to enhance LTD glu . In this respect, LTD glu enhancement is clearly distinguished from the previously reported GABA B R-mediated augmentation of an mGluR1-coupled slow excitatory postsynaptic potential. Baclofen application for only the induction period of LTD glu was sufficient to enhance LTD glu , suggesting that GABA B R signalling may modulate mechanisms underlying LTD glu induction. Baclofen augmented mGluR1-coupled Ca 2+ release from the intracellular stores in a G i/o protein-dependent manner. Therefore, GABA B R-mediated LTD glu enhancement is likely to result from augmentation of mGluR1 signalling. Furthermore, pharmacological inhibition of GABA B R reduced the magnitude of LTD at parallel fibre-Purkinje cell synapses in cerebellar slices. These findings demonstrate a novel mechanism that would facilitate cerebellar motor learning.

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“…Likewise slow IPSCs were partially suppressed by GIRK channel blockers tertiapin-Q (100 nM, n=5, 55 ± 0.1% at 15 minutes) and SCH23390 (10 μM, n=6, 54 ± 0.1% at 12 minutes) (Fink, et al, 2007, Jelacic, et al, 2000, Kuzhikandathil and Oxford, 2002). Incomplete block of slow IPSCs by GIRK channel blockers may be due to heterogenous GABA B postsynaptic currents, partial block, or use dependence (Best, et al, 2007, Kanjhan, et al, 2005, Pham, et al, 1998, Tabata, et al, 2005). Additionally, since SCH23390 is a known dopamine D1 and D5 receptor antagonist as well as an agonist at serotonin 5HT 1C and 5HT 2C receptors, the involvement of these receptors may play a role in the partial block (Bourne, 2001, Briggs, et al, 1991, Millan, et al, 2001).…”

Section: Methodsmentioning

confidence: 99%

Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome

Best

Cramer

Chakrabarti

et al. 2012

Experimental Neurology

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GABAergic dysfunction is implicated in hippocampal deficits of the Ts65Dn mouse model of Down syndrome (DS). Since Ts65Dn mice overexpress G-protein coupled inward-rectifying potassium (GIRK2) containing channels, we sought to evaluate whether increased GABAergic function disrupts the functioning of hippocampal circuitry. After confirming that GABAB/GIRK current density is significantly elevated in Ts65Dn CA1 pyramidal neurons, we compared monosynaptic inhibitory inputs in CA1 pyramidal neurons in response to proximal (stratum radiatum; SR) and distal (stratum lacunosum moleculare; SLM) stimulation of diploid and Ts65Dn acute hippocampal slices. Synaptic GABAB and GABAA mediated currents evoked by SR stimulation were generally unaffected in Ts65Dn CA1 neurons. However, the GABAB/GABAA ratios evoked by stimulation within the SLM of Ts65Dn hippocampus were significantly larger in magnitude, consistent with increased GABAB/GIRK currents after SLM stimulation. These results indicate that GIRK overexpression in Ts65Dn has functional consequences which affect the balance between GABAB and GABAA inhibition of CA1 pyramidal neurons, most likely in a pathway specific manner, and may contribute to cognitive deficits reported in these mice.

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GABAergic activation of an inwardly rectifying K⁺ current in mouse cerebellar Purkinje cells

Cited by 31 publications

References 56 publications

Targeting potassium channels to treat cerebellar ataxia

Targeting potassium channels to treat cerebellar ataxia

Postsynaptic GABA_B receptor signalling enhances LTD in mouse cerebellar Purkinje cells

Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome

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GABAergic activation of an inwardly rectifying K+ current in mouse cerebellar Purkinje cells

Cited by 31 publications

References 56 publications

Targeting potassium channels to treat cerebellar ataxia

Targeting potassium channels to treat cerebellar ataxia

Postsynaptic GABAB receptor signalling enhances LTD in mouse cerebellar Purkinje cells

Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome

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GABAergic activation of an inwardly rectifying K⁺ current in mouse cerebellar Purkinje cells

Postsynaptic GABA_B receptor signalling enhances LTD in mouse cerebellar Purkinje cells