RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion

Abstract

Parkinson disease is a neurodegenerative disorder whose symptoms are caused by the loss of dopaminergic neurons innervating the striatum. As striatal dopamine levels fall, striatal acetylcholine release rises, exacerbating motor symptoms. This adaptation is commonly attributed to the loss of interneuronal regulation by inhibitory D(2) dopamine receptors. Our results point to a completely different, new mechanism. After striatal dopamine depletion, D(2) dopamine receptor modulation of calcium (Ca(2+)) channels controlling vesicular acetylcholine release in interneurons was unchanged, but M(4) muscarinic autoreceptor coupling to these same channels was markedly attenuated. This adaptation was attributable to the upregulation of RGS4-an autoreceptor-associated, GTPase-accelerating protein. This specific signaling adaptation extended to a broader loss of autoreceptor control of interneuron spiking. These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease.

Involvement of Striatal Cholinergic Interneurons and M1 and M4 Muscarinic Receptors in Motor Symptoms of Parkinson's Disease

“…M4 mAChRs activate Gi/o proteins and are located in the striatum presynaptically on striatal ChI terminals, where they function as cholinergic autoreceptors inhibiting ACh release, along with M2 mAChRs (Kreitzer, 2009), and postsynaptically on D1-MSNs, where their activation results, among other mechanisms, in Cav2 channel inhibition and therefore shapes the spiking of MSNs (Santiago and Potter, 2001;. The loss of striatal DA has been reported to attenuate M4 autoreceptor signaling in ChIs, which might be a main factor in elevated striatal ACh release after DA depletion (Ding et al, 2006). Such adaptation is likely to limit the outcomes of M4 autoreceptor antagonism, which should otherwise have proparkinsonian rather than anti-parkinsonian action.…”

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

“…RGS4 has been reported to be enriched and widely expressed in the mammalian brain (Erdely et al, 2004;Ebert et al, 2006a;Ebert et al, 2006b), making it particularly relevant for brain tumour research. Furthermore, changes in RGS4 expression or activity have been linked to other major CNS disorders, including Parkinson's disease (Ding et al, 2006), schizophrenia (Levitt et al, 2006), and drug addiction (Hooks et al, 2008).…”

Differential involvement of M1-type and M4-type muscarinic cholinergic receptors in the dorsomedial striatum in task switching

“…The doses of MT-3 infused into the dorsomedial striatum and post-injection test periods used in the present study are comparable to those used in previous studies in which MT-3 was found to affect learning or memory (Diehl et al, 2007;Ferreira et al, 2003). There is evidence that a significant portion of M4-type receptors expressed in the striatum are on cholinergic interneurons acting as autoreceptors (Ding, Guzman, Tkatch, Chen, Goldberg, Ebert, Levitt, Wilson, Hamm & Surmeier, 2006). This raises the possibility that blockade of M4-type receptors in the dorsomedial striatum should facilitate ACh release and potentially lead to an enhancement of reversal learning.…”