Involvement of HCN Channel in Muscarinic Inhibitory Action on Tonic Firing of Dorsolateral Striatal Cholinergic Interneurons

Zhao, Zhe; Zhang, Kang; Liu, Xiaoyan; Yan, Hang; Ma, Xiaoyun; Zhang, Shuzhuo; Zheng, Jiawei; Wang, Liyun; Wei, Xiaoli

doi:10.3389/fncel.2016.00071

Cited by 33 publications

(49 citation statements)

References 98 publications

(162 reference statements)

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“…KCNQ2/3 and HCN2 channels in CINs underlie the I Kr and the I h , respectively. Whilst our results show no difference in their expression in the absence of Er81, these voltage-sensitive channels could be modulated by second messengers such as phosphatidylinositol-4,5-bisphosphate (PIP 2 ) and calcium for KCNQ2/3 (Wilson and Goldberg, 2006) (Falkenburger et al, 2010) , and cAMP for HCN2 (Zhao et al, 2016) (Alvarez-Baron et al, 2018. We propose that the enhanced I Kr in the Er81 cKO cells is due to a higher intracellular calcium concentration mediated through mGluR5 (Niswender and Conn, 2010).…”

Section: Mechanisms Regulating Tonic and Phasic Activity Of The Striacontrasting

confidence: 57%

“…Consistently, we also found significantly larger I h current amplitude in the Er81 cKO compared to the control CINs (Figure 4D-F). The hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 1 and 2 (HCN1 and HCN2) are the main channel subunits underlying the I h current in the CINs (Zhao et al, 2016). Therefore, we examined whether a potential increase in the expression of these proteins contributes to the enhanced I h current we observed in the Er81 cKO condition.…”

Section: Introductionmentioning

confidence: 99%

“…The pause in CIN firing is fundamental for striatal processing of information and behaviour . 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).…”

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: Mechanisms Regulating Tonic and Phasic Activity Of The Striacontrasting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

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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“…ChIs express high levels of dopamine D2Rs and M2/M4 mACh autoreceptors (Yan and Surmeier, 1996; Straub et al, 2014; Wieland et al, 2014). D2Rs and M2/M4 mAChRs reduce tonic firing of ChIs, and subsequent ACh release, through shared coupling to G i/o signaling, which diminishes the opening of Cav2 Ca 2+ channels in response to membrane depolarization (Yan and Surmeier, 1996; Yan et al, 1997; Calabresi et al, 1998; Maurice et al, 2004; Ding et al, 2006; Bonsi et al, 2008; Zhao et al, 2016). In vivo microdialysis (Drukarch et al, 1990; Stoof et al, 1992b; DeBoer and Abercrombie, 1996) and electrophysiological (Yan et al, 1997) studies revealed that the ability of the D2R agonist quinpirole to decrease ACh release and to reduce Ca 2+ currents in ChIs is limited by increasing levels of striatal ACh, suggesting that dopamine modulation of striatal ACh release is influenced by striatal cholinergic tone, perhaps through functional interactions between D2R and M2/M4 mACh autoreceptors.…”

Section: Introductionmentioning

confidence: 99%

Strength of cholinergic tone dictates the polarity of dopamine D2 receptor modulation of striatal cholinergic interneuron excitability in DYT1 dystonia

Scarduzio

Zimmerman

Jaunarajs

et al. 2017

Experimental Neurology

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Balance between cholinergic and dopaminergic signaling is central to striatal control of movement and cognition. In dystonia, a common disorder of movement, anticholinergic therapy is often beneficial. This observation suggests there is a pathological increase in cholinergic tone, yet direct confirmation is lacking. In DYT1, an early-onset genetic form of dystonia caused by a mutation in the protein torsinA (TorA), the suspected heightened cholinergic tone is commonly attributed to faulty dopamine D2 receptor (D2R) signaling where D2R agonists cause excitation of striatal cholinergic interneurons (ChIs), rather than the normal inhibition of firing observed in wild-type animals, an effect known as “paradoxical excitation”. Here, we provide for the first time direct measurement of elevated striatal extracellular acetylcholine (ACh) in a knock-in mouse model of human DYT1 dystonia (TorAΔE/+ mice), confirming a striatal hypercholinergic state. We hypothesized that this elevated extracellular ACh might cause chronic over-activation of muscarinic acetylcholine receptors (mAChRs) and disrupt normal D2R function due to their shared coupling to Gi/o-proteins. We tested this concept in vitro first using a broad-spectrum mAChR antagonist, and then using a M2/M4 mAChR selective antagonist to specifically target mAChRs expressed by ChIs. Remarkably, we found that mAChR inhibition reverses the D2R–mediated paradoxical excitation of ChIs recorded in slices from TorAΔE/+ mice to a typical inhibitory response. Furthermore, we recapitulated the paradoxical D2R excitation of ChIs in striatal slices from wild type mice within minutes by simply increasing cholinergic tone through pharmacological inhibition of acetylcholinesterase (AChE) or by prolonged agonist activation of mAChRs. Collectively, these results show that enhanced mAChR tone itself is sufficient to rapidly reverse the polarity of D2R regulation of ChI excitability, correcting the previous notion that the D2R mediated paradoxical ChI excitation causes the hypercholinergic state in dystonia. Further, using a combination of genetic and pharmacological approaches, we found evidence that this switch in D2R polarity results from a change in coupling from the preferred Gi/o pathway to non-canonical β-arrestin signaling. These results highlight the need to fully understand how the mutation in TorA leads to pathologically heightened extracellular ACh. Furthermore the discovery of this novel ACh-dopamine interaction and the participation of β-arrestin in regulation of cholinergic interneurons is likely important for other basal ganglia disorders characterized by perturbation of ACh-dopamine balance, including Parkinson and Huntington diseases, l-DOPA-induced dyskinesia and schizophrenia.

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“…The procedures were similar to those we described previously (Zhao et al, 2016). In brief, male Sprague Dawley rats (14–16 days old) were decapitated.…”

Section: Methodsmentioning

confidence: 99%

Sigma-1 Receptor Plays a Negative Modulation on N-type Calcium Channel

Zhang¹,

Zhao

Lan³

et al. 2017

Front. Pharmacol.

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The sigma-1 receptor is a 223 amino acids molecular chaperone with a single transmembrane domain. It is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes. By chaperone-mediated interactions with ion channels, G-protein coupled receptors and cell-signaling molecules, the sigma-1 receptor performs broad physiological and pharmacological functions. Despite sigma-1 receptors have been confirmed to regulate various types of ion channels, the relationship between the sigma-1 receptor and N-type Ca2+ channel is still unclear. Considering both sigma-1 receptors and N-type Ca2+ channels are involved in intracellular calcium homeostasis and neurotransmission, we undertake studies to explore the possible interaction between these two proteins. In the experiment, we confirmed the expression of the sigma-1 receptors and the N-type calcium channels in the cholinergic interneurons (ChIs) in rat striatum by using single-cell reverse transcription-polymerase chain reaction (scRT-PCR) and immunofluorescence staining. N-type Ca2+ currents recorded from ChIs in the brain slice of rat striatum was depressed when sigma-1 receptor agonists (SKF-10047 and Pre-084) were administrated. The inhibition was completely abolished by sigma-1 receptor antagonist (BD-1063). Co-expression of the sigma-1 receptors and the N-type calcium channels in Xenopus oocytes presented a decrease of N-type Ca2+ current amplitude with an increase of sigma-1 receptor expression. SKF-10047 could further depress N-type Ca2+ currents recorded from oocytes. The fluorescence resonance energy transfer (FRET) assays and co-immunoprecipitation (Co-IP) demonstrated that sigma-1 receptors and N-type Ca2+ channels formed a protein complex when they were co-expressed in HEK-293T (Human Embryonic Kidney -293T) cells. Our results revealed that the sigma-1 receptors played a negative modulation on N-type Ca2+ channels. The mechanism for the inhibition of sigma-1 receptors on N-type Ca2+ channels probably involved a chaperone-mediated direct interaction and agonist-induced conformational changes in the receptor-channel complexes on the cell surface.

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Involvement of HCN Channel in Muscarinic Inhibitory Action on Tonic Firing of Dorsolateral Striatal Cholinergic Interneurons

Cited by 33 publications

References 98 publications

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

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

Strength of cholinergic tone dictates the polarity of dopamine D2 receptor modulation of striatal cholinergic interneuron excitability in DYT1 dystonia

Sigma-1 Receptor Plays a Negative Modulation on N-type Calcium Channel

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