Pauses in Cholinergic Interneuron Activity Are Driven by Excitatory Input and Delayed Rectification, with Dopamine Modulation

Zhang, Yan-Feng; Reynolds, John N. J.; Cragg, Stephanie J.

doi:10.1016/j.neuron.2018.04.027

Cited by 57 publications

(85 citation statements)

References 57 publications

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“…Together, our results indicate that the initial responsiveness of the CINs is not altered, but their overall excitability is reduced due to stronger firing rate adaptations in the absence of Er81 (Figure 3D). It has been shown that CIN firing rate is controlled by the large, calcium-dependent delayed rectifier current I Kr (Zhang et al, 2018) (Wilson and Goldberg, 2006). Therefore, the observed differences ( Figure 3B) might be due to an increase in the I Kr current in the Er81 cKO conditions.…”

Section: Introductionmentioning

confidence: 92%

“…In order to decipher the molecular mechanisms behind this regulation, we first analysed the expression of previously identified I Kr mediators in CINs, the KCNQ2/3 hetero-tetramer channels (Zhang et al, 2018). We found a significant decrease in KCNQ2 mRNA levels ( Figure 3H), without any change in KCNQ2 protein levels (Figure 3I & J) between the P30 control and Er81 cKO mice.…”

Section: Introductionmentioning

confidence: 93%

“…For the first time, our findings link the Er81 transcription factor with intrinsic currents and plasticity-related receptors such as mGluR5, and provide a basis to determine which molecular factors contribute to the emergence of the unique properties of striatal CINs. Elevated I Kr and I h currents, together with larger inhibitory inputs on CINs, can explain the sharper firing dynamics and higher correlations of the putative CINs activity with sensorimotor inputs in vivo in the absence of Er81 (Bennett et al, 2000) (Wilson and Goldberg, 2006) (Zhang et al, 2018). KCNQ2/3 and HCN2 channels in CINs underlie the I Kr and the I h , respectively.…”

Section: Mechanisms Regulating Tonic and Phasic Activity Of The Striamentioning

confidence: 98%

“…Intrinsic electrophysiological properties are responsible for maintaining tonic activity of striatal CINs (Bennett et al, 2000). Together with synaptic inputs (Franklin and Frank, 2015) ( Klug et al, 2018), they also contribute to the phasic response to stimuli (Zhang et al, 2018).…”

Section: Mechanisms Regulating Tonic and Phasic Activity Of The Striamentioning

confidence: 99%

“…The tonic and phasic activity of CINs are governed by both synaptic inputs and the intrinsic inward (Zhao et al, 2016) and delayed rectifier currents (Wilson and Goldberg, 2006). In particular, pause expression is mediated by the slow Kv7mediated potassium current I Kr in response to excitatory inputs and is regulated by dopamine (Zhang et al, 2018). Yet, the role of intrinsic molecular factors in regulating CIN pauses remains unexplored.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 93%