GABA transporter 1 tunes GABAergic synaptic transmission at output neurons of the mouse neostriatum

Kirmse, Knut; Dvorzhak, Anton; Kirischuk, Sergei; Grantyn, Rosemarie

doi:10.1113/jphysiol.2008.161943

Cited by 44 publications

(79 citation statements)

References 54 publications

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“…Parasagittal brain slices (300 μm thick) were prepared, as described (43), from transgenic R6/2 mice and their WT (CBA × C57BL/6J) littermates (postnatal days 25-57) as described (43), and from BACHD mice and their WT littermates (FVB/N). Animals were bred and genotyped at Jackson Labs and provided by the CHDI Foundation.…”

Section: Methodsmentioning

confidence: 99%

Rescue of homeostatic regulation of striatal excitability and locomotor activity in a mouse model of Huntington’s disease

Cao

Bartolomé-Martı́n

Rotem

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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We describe a fast activity-dependent homeostatic regulation of intrinsic excitability of identified neurons in mouse dorsal striatum, the striatal output neurons. It can be induced by brief bursts of activity, is expressed on a time scale of seconds, limits repetitive firing, and can convert regular firing patterns to irregular ones. We show it is due to progressive recruitment of the KCNQ2/3 channels that generate the M current. This homeostatic mechanism is significantly reduced in striatal output neurons of the R6/2 transgenic mouse model of Huntington's disease, at an age when the neurons are hyperactive in vivo and the mice begin to exhibit locomotor impairment. Furthermore, it can be rescued by bath perfusion with retigabine, a KCNQ channel activator, and chronic treatment improves locomotor performance. Thus, M-current dysfunction may contribute to the hyperactivity and network dysregulation characteristic of this neurodegenerative disease, and KCNQ2/3 channel regulation may be a target for therapeutic intervention.untington's disease (HD) is a fatal inherited autosomal neurodegenerative disorder, with its primary symptoms being progressive development of motor and cognitive dysfunction (1). The mutated gene, huntingtin (HTT), and its mutation, an expansion of the number of CAG repeats, were identified 20 y ago. However, the mechanism(s) underlying the pathological changes that culminate in the degeneration of striatal output neurons (SONs) remain unknown. Early animal models (2) generated a number of testable hypotheses, most notable being that the neurons degenerate because of a hyperactivity that leads to a build-up of excitotoxic molecules. However, more recent studies implicate alternative pathologies, such as altered transcriptional activity, calcium regulation and mitochondrial function, or disruptions in normal neuronal patterns of activity (3) and show that neuronal dysfunction and behavioral and motor symptoms of HD precede neurodegeneration (2). These studies have been facilitated by access to transgenic mice models, including R6/1 and R6/2 mice, which express a truncated region of the mutant human HTT gene with expanded CAG repeats (4). In vitro recordings in both lines revealed that SONs are depolarized and have higher input resistances than do wild-type (WT) controls, at a stage where deficits in locomotor activity begin to be manifest (5-7). Furthermore, in vivo recordings indicate that at 5-9 wk of age, when the mice exhibit overt motor deficits, R6/2 SONs have higher firing rates and more regular discharge patterns compared with WT (8, 9). In contrast, neurodegeneration and death occur later (2). Hence, we asked whether cellular mechanisms that influence excitability might be altered in the early stages of HD and might serve as targets for alleviating associated behavioral symptoms.Hyperactivity and related changes in neuronal firing patterns could reflect alterations in synaptic transmission and its activitydependent modifications or in intrinsic membrane properties governing neuronal e...

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Section: Methodsmentioning

confidence: 99%

Rescue of homeostatic regulation of striatal excitability and locomotor activity in a mouse model of Huntington’s disease

Cao

Bartolomé-Martı́n

Rotem

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Vicini's (Ade et al 2008;Janssen et al 2009;Janssen et al 2011;Luo et al 2013) and other groups (Kirmse et al 2008;Janssen et al 2009;Santhakumar et al 2010) have provided solid evidence for the presence and the developmental profile of a tonic GABA A current in MSNs. (Note, however, that one study did not find any evidence for a tonic GABA A current in D2 + or D1 + MSNs; Gertler et al 2008.)…”

Section: Striatummentioning

confidence: 96%

GPCR Modulation of Extrasynapitic GABAA Receptors

Connelly

Errington

Yagüe

et al. 2014

Extrasynaptic GABAA Receptors

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γ-Aminobutyric acid type A (GABA A ) receptors (GABA A Rs), the main inhibitory neurotransmitter-gated ion channels in the central nervous system, are finely tuned by other neurotransmitters and endogenous ligands. The regulation of synaptic GABA A Rs (sGABA A Rs) by G protein-coupled receptors (GPCRs) has been well characterized and is known to occur either through the conventional activation of second-messenger signalling cascades by G proteins or directly by protein-protein coupling. In contrast, research on the modulation of extrasynaptic GABA A R (eGABA A Rs) is still in its infancy and it remains to be determined whether both of the above mechanisms are capable of controlling eGABA A R function. In this chapter, we summarize the available literature on eGABA A R modulation by GPCRs, including GABA B , serotonin (5-HT), dopamine (DA), noradrenaline (NA) and metabotropic glutamate (mGlu) receptors. Although at present these GPCRs-eGABA A Rs cross-talks have been investigated in a limited number of brain areas (i.e., thalamus, cerebellum, hippocampus, striatum), it is already evident that eGABA A Rs show a nucleus-and neuronal type-selective regulation by GPCRs that differs from that of sGABA A Rs. This distinct regulation of eGABA A Rs versus sGABA A Rs by GPCRs provides mechanisms for receptor adaptation in response

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“…Many groups ( Ade et al, 2008 ;Kirmse et al, 2008 ;Janssen et al, 2009Janssen et al, , 2011Santhakumar et al, 2010 ;Luo et al, 2013 ) have shown the presence of a tonic GABA A current in MSNs, although one study ( Gertler et al, 2008 ) did not report a tonic GABA A current in either D2 + or D1 + MSNs. D2 + MSNs have a greater tonic GABA A current ( Zheng and Johnson, 2001 ) and are more sensitive to low doses of GABA than D1 + MSNs ( Ade et al, 2008 ).…”

Section: Striatummentioning

confidence: 99%