GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease

Lozovaya, Natalia; Eftekhari, Sanaz; Cloarec, Robin; Gouty‐Colomer, Laurie‐Anne; Dufour, Amandine; Riffault, Baptiste; Billon-Grand, M.; Pons-Bennaceur, Alexandre; Oumar, N.; Burnashev, Nail; Hammond, Constance

doi:10.1038/s41467-018-03802-y

Cited by 76 publications

(101 citation statements)

References 61 publications

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“…Additionally, the loss of DA may change the response of striatal neurons to acetylcholine as the degree of muscarinic and nicotinic acetylcholine receptor binding is altered in the brain tissue of PD patients (Aubert et al, 1992;Joyce, 1993;Pimlott et al, 2004) and after experimental DA depletion (Cremer et al, 2015;Joyce, 1991). Combined with the dendritic remodeling observed in our results ( Figure 3) and other studies (Lozovaya et al, 2018), and changes in the connectivity from ChIs to spiny projection neurons (Salin et al, 2009) that may drive changes in the regulation of neurotransmitter release from striatonigral synapses (Borgkvist et al, 2015), it is likely that the regulation of striatal output by ChIs is perturbed as a result.…”

Section: Changes In Chi Tonic Activity Following Da Depletion and Chrsupporting

confidence: 81%

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA

Choi

Ding

et al. 2020

Preprint

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Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson's disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes are unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was due to decreased currents of both hyperpolarization-activated cyclic nucleotide-gated (HCN) and small conductance calcium-activated potassium (SK) channels. L-DOPA reinstatement of dopamine normalized HCN activity, but SK current remained depressed. Pharmacological blockade of HCN and SK activities mimicked changes in firing, confirming that these channels are responsible for the molecular adaptation of ChIs to dopamine loss and chronic L-DOPA treatment. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients.

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Section: Changes In Chi Tonic Activity Following Da Depletion and Chrsupporting

confidence: 81%

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA

Choi

Ding

et al. 2020

Preprint

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“…Lhx6 is expressed in about half of striatal CINs (Lozovaya et al, 2018)and is necessary for MGE-derived GABAergic interneuron specification (Liodis et al, 2007) (Fragkouli et al, 2009) (Flandin et al, 2011. We first examined whether the expression of Lhx6 and Er81 were correlated in the striatal CINs.…”

Section: Cholinergic Interneuron Properties Change In the Absence Ofmentioning

confidence: 99%

“…The functional implications of molecular heterogeneity in striatal CINs are at present not well understood (Munoz-Manchado et al, 2018) (Lozovaya et al, 2018) (Magno et al, 2017). CINs originate from distinct areas of the subpallium which give rise to heterogeneous populations of cholinergic cells in the forebrain (Ahmed et al, 2019).…”

Section: Control Of the Cholinergic Cell Identitymentioning

confidence: 99%

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Loss of the Er81 Transcription Factor in Cholinergic Cells Alters Striatal Activity and Habit Formation

Ranjbar-Slamloo

Ahmed

Abed

et al. 2020

Preprint

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Highlights-The Er81 transcription factor is expressed in striatal cholinergic interneurons (CINs) -Conditional deletion of Er81 alters key molecular, morphological and electrophysiological properties of CINs in adult mice -Deletion of Er81 reduces the intrinsic excitability of CINs by upregulating delayed rectifier and hyperpolarization-activated currents -Deletion of Er81 alters in vivo striatal activity and habit formation SUMMARYThe finely-tuned activity of cholinergic interneurons (CINs) in the striatum is key for motor control, learning, and habit formation. Yet, the molecular mechanisms that determine their unique functional properties remain poorly explored. Using a combination of genetic and biochemical assays, in vitro and in vivo physiological characterisation, we report that selective ablation of the Er81 transcription factor leads to prominent changes in CIN molecular, morphological and electrophysiological features. In particular, the lack of Er81 amplifies intrinsic delayed-rectifier and hyperpolarization-activated currents, which subsequently alters the tonic and phasic activity of CINs. We further demonstrate that these alterations enhance their pause and time-locked responses to sensorimotor inputs in awake mice. Finally, this study reveals an Er81-dependent developmental mechanism in CINs essential for habit formation in adult mice. RESULTS Er81 is expressed in the striatal cholinergic interneuronsWe first analysed the expression of Er81 from birth to adulthood and found that both mRNA ( Figure 1A) and protein levels (Figure 1B) significantly drop from postnatal day 6 (P6) to P30 in the total striatum. In the CINs specifically, we observed similar decrease of Er81 protein levels from P6 to P30 (Figure 1C). To determine the proportion of CINs expressing Er81 at any stage during development, we analysed β-galactosidase staining, which perdures long after being synthesised (Dehorter et al., 2015). We found that most of CINs (62 ± 7 %) in the Er81 nlsLacZ/+ mice express β-galactosidase (and therefore Er81) in the striatum (Figure S1A), unlike cholinergic cells in the basal forebrain (6 ± 2%; Figure S1B). As Er81 can have an important role in cell function (Dehorter et al., 2015), we analysed the consequences of removing Er81 from CINs, using conditional knockout mice (cKO: ChAT-Cre; Er81 f/f ; comparing with control mice: ChAT-Cre; Er81 +/+ ). We did not observe any change in cholinergic cell density at P2 and P30 within the striatum between control and Er81 cKO conditions (Figure 1D-Fsuggesting that the specific deletion of Er81 does not affect CIN neurogenesis and migration. Cholinergic interneuron properties change in the absence of Er81To determine the role of Er81 in CIN specification and maturation, we assessed the molecular properties of these cells following Er81 deletion. The LIM homeodomain transcription factorLhx6 is expressed in about half of striatal CINs (Lozovaya et al., 2018)and is necessary for MGE-derived GABAergic interneuron specification (Liodis et al., 2007) (Fragkouli et al., ...

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“…spontaneous (Kaeser and Regehr, 2013), as reported previously for tonic inhibition of SPNs (Wójtowicz et al, 2013). A spontaneous GABAergic regulation of DA release is not surprising when considering that the axonal arbour of a given nigrostriatal DA neuron (in rat) reaches on average 2.7% of the volume of striatum (Matsuda et al, 2009;Oorschot, 1996), and that such volumes contain ~74,000 GABAergic neurons (calculated from 2.8 million striatal neurons per hemisphere (Oorschot, 1996), of which ~98% are GAD-immunoreactive) and also GAD-positive cholinergic interneurons that can corelease GABA (Lozovaya et al, 2018). Even very low rates of spontaneous vesicle release from a small fraction of GAD-utilizing GABAergic neurons might summate sufficiently to provide a tone at GABA receptors on DA axons that limits DA output.…”

Section: Gats Limits the Tonic Inhibition Of Da Releasementioning

confidence: 99%

Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism

Roberts

Doig

Brimblecombe

et al. 2019

Preprint

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Striatal dopamine (DA) is critical for action and learning. Recent data show DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be governed by plasma membrane GABA uptake transporters (GATs) on astrocytes. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs were downregulated and tonic GABAergic inhibition of DA release augmented, with corresponding attenuation of GABA co-release from dopaminergic axons. These data define previously unappreciated and important roles for GATs and astrocytes in determining DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.

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GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease

Cited by 76 publications

References 61 publications

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA

Loss of the Er81 Transcription Factor in Cholinergic Cells Alters Striatal Activity and Habit Formation

Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism

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