M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia

Shen, Weisen; Plotkin, Joshua L.; Francardo, Veronica; Ko, Wai Kin D.; Xie, Zhong; Li, Qin; Fieblinger, Tim; Wess, Jürgen; Neubig, Richard R.; Lindsley, Craig W.; Conn, P. Jeffrey; Greengard, Paul; Bézard, Erwan; Cenci, M. Angela; Surmeier, D. James

doi:10.1016/j.neuron.2016.05.017

Cited by 55 publications

(108 citation statements)

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“…Although the rate and timing of neuronal activity may be important for information processing, there is no consensus on a reliable D2R-dependent LTD-producing spike-timing dependent plasticity (STDP) protocol among the few groups that have used this protocol to assess corticostriatal plasticity (Fino et al, 2005; Nazzaro et al, 2012; Pawlak and Kerr, 2008; Shen et al, 2008, 2016). As a result, we decided to use a conventional stimulation protocol, HFS, which has been used by many laboratories and reliably induces D2R-dependent LTD (Augustin et al, 2014; Calabresi et al, 1994; Choi and Lovinger, 1997; Kreitzer and Malenka, 2005; Lerner and Kreitzer, 2012; Wang et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons

2018

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SUMMARY Endocannabinoid (eCB)-mediated long-term depres-sion (LTD) requires dopamine (DA) D2 receptors (D2Rs) for eCB mobilization. The cellular locus of the D2Rs involved in LTD induction remains highly debated. We directly examined the role in LTD induc-tion of D2Rs expressed by striatal cholinergic inter-neurons (Chls) and indirect pathway medium spiny neurons (iMSNs) using neuron-specific targeted deletion of D2Rs. Deletion of Chl-D2Rs (Chl-Drd2KO) impaired LTD induction in both subtypes of MSNs. LTD induction was restored in the Chl-Drd2KO mice by an M1-selective muscarinic acetylcholine receptor antagonist. In contrast, after the deletion of iMSN-D2Rs (iMSN-Drd2KO), LTD induction was intact in MSNs. Separate interrogation of direct pathway and iMSNs revealed a deficit in LTD induction only at syn-apses onto iMSNs that lack D2Rs. LTD induction in iMSNs was restored by D2R agonist application. Our findings suggest that Chl D2Rs strongly modulate LTD induction in MSNs, with iMSN-D2Rs having a weaker, iMSN-specific, modulatory effect.

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Section: Discussionmentioning

confidence: 99%

Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons

2018

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“…Activation of these receptors is well known to increases MSN excitability (Galarraga et al ., ; Perez‐Rosello et al ., ; Xiang et al ., ; Lv et al ., ). By contrast, M4 mAChRs are known to be preferentially expressed on D1 MSNs, where upon activation they decrease the excitability of these neurons, thus facilitating long‐term depotentiation (LTD) in D1 MSNs (Bernard et al ., ; Hersch et al ., ; Howe & Surmeier, ; Jeon et al ., ; Shen et al ., ; Moehle et al ., ). This concerted action of ACh at M1 and M4 mAChRs effectively controls MSN activity.…”

Section: Enhanced Chi Activity In Lids Expressionmentioning

confidence: 98%

Cholinergic control of striatal neurons to modulate L‐dopa‐induced dyskinesias

Bordia

Perez

2018

Eur J of Neuroscience

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L-dopa induced dyskinesias (LIDs) are a disabling motor complication of L-dopa therapy for Parkinson's disease (PD) management. Treatment options remain limited and the underlying network mechanisms remain unclear due to a complex pathophysiology. What is well-known, however, is that aberrant striatal signaling plays a key role in LIDs development. Here, we discuss the specific contribution of striatal cholinergic interneurons (ChIs) and GABAergic medium spiny projection neurons (MSNs) with a particular focus on how cholinergic signaling may integrate multiple striatal systems to modulate LIDs expression. Enhanced ChI transmission, altered MSN activity and the associated abnormal downstream signaling responses that arise with nigrostriatal damage are well known to contribute to LIDs development. In fact, enhancing M4 muscarinic receptor activity, a receptor favorably expressed on D1 dopamine receptor-expressing MSNs dampens their activity to attenuate LIDs. Likewise, ChI activation via thalamostriatal neurons is shown to interrupt cortical signaling to enhance D2 dopamine receptor-expressing MSN activity via M1 muscarinic receptors, which may interrupt ongoing motor activity. Notably, numerous preclinical studies also show that reducing nicotinic cholinergic receptor activity decreases LIDs. Taken together, these studies indicate the importance of cholinergic control of striatal neuronal activity and point to muscarinic and nicotinic receptors as significant pharmacological targets for alleviating LIDs in PD patients.

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“…M 4 receptors are present on cortico-striatal terminals, and activation of these presynaptic M 4 receptors may contribute to M 4 PAM effects at these excitatory synapses (Pancani et al, 2014). However, as with the effect of M 4 PAMs on DA release, the ability of M 4 PAMs to induce LTD in D 1 -SPNs is absent in D 1 -M 4 -/- mice and, surprisingly, was blocked by a CB 1 receptor antagonist (Shen et al, 2016), suggesting M 4 PAM-induced eCB release from D 1 -SPNs can inhibit excitatory transmission in the striatum. Extensive studies in rodents and non-human primates suggest that these actions of M 4 PAMs on striatal plasticity could provide therapeutic benefits in treating L-DOPA-induced dyskinesia in Parkinson's disease (Shen et al, 2016).…”

Section: Potential Utility Of Muscarinic Receptor Pams For Treatment mentioning

confidence: 96%

“…However, as with the effect of M 4 PAMs on DA release, the ability of M 4 PAMs to induce LTD in D 1 -SPNs is absent in D 1 -M 4 -/- mice and, surprisingly, was blocked by a CB 1 receptor antagonist (Shen et al, 2016), suggesting M 4 PAM-induced eCB release from D 1 -SPNs can inhibit excitatory transmission in the striatum. Extensive studies in rodents and non-human primates suggest that these actions of M 4 PAMs on striatal plasticity could provide therapeutic benefits in treating L-DOPA-induced dyskinesia in Parkinson's disease (Shen et al, 2016). Furthermore, M 4 PAMs can normalize excessive excitatory transmission at cortico-striatal synapses in rodent models of Huntington's disease and chronic administration of M 4 PAMs prevents the appearance of motor deficits in these animals (Pancani et al, 2015).…”

Section: Potential Utility Of Muscarinic Receptor Pams For Treatment mentioning

confidence: 96%

“…In addition to regulation of DA release, recent studies reveal that M 4 PAMs can decrease glutamatergic transmission at cortico-striatal synapses (Pancani et al, 2014) and induce spike-timing dependent LTD on D 1 -SPNs (Shen et al, 2016). M 4 receptors are present on cortico-striatal terminals, and activation of these presynaptic M 4 receptors may contribute to M 4 PAM effects at these excitatory synapses (Pancani et al, 2014).…”

Section: Potential Utility Of Muscarinic Receptor Pams For Treatment mentioning

confidence: 99%

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Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

Foster

Conn

2017

Neuron

203

171

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G-protein coupled receptors (GPCRs) play critical roles in regulating brain function. Recent advances have greatly expanded our understanding of these receptors as complex signaling machines that can adopt numerous conformations and modulate multiple downstream signaling pathways. While agonists and antagonists have traditionally been pursued to target GPCRs, allosteric modulators provide several mechanistic advantages including the ability to distinguish between closely related receptor subtypes. Recently, the discovery of allosteric ligands that confer bias and modulate some, but not all, of a given receptor's downstream signaling pathways can provide pharmacological modulation of brain circuitry with remarkable precision. In addition, allosteric modulators with unprecedented specificity have been developed that can differentiate between subpopulations of a given receptor subtype based on the receptor's dimerization state. These advances are not only providing insight into the biological roles of specific receptor populations, but hold great promise for treating numerous CNS disorders.

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M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia

Cited by 55 publications

References 0 publications

Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons

Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons

Cholinergic control of striatal neurons to modulate L‐dopa‐induced dyskinesias

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

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