Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1

Abstract

BackgroundSpinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1.ResultsSymptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells.ConclusionsThese data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel “cerebellum-specific”, effective, and safe symptomatic drugs for the treatment of SCA1 in humans.

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

“…185–188 However, as the only available mGlu 1 PAM in vivo tool, it has been employed to preclinically validate mGlu 1 in multiple CNS disorders. 189–192 With the new emphasis on genetic basis of disease, two recent, independent studies identified 12 rare, deleterious nonsynonymous single-nucleotide polymorphisms (nsSNPs) in the GRM1 gene, which encodes mGlu 1 , in schizophrenic patients; this has renewed interest in mGlu 1 PAMs, as these mutations were shown to be loss of function. 193,194 Work from the Vanderbilt group has characterized the mutant mGlu 1 receptors and demonstrated that 38 could indeed potentiate their response to glutamate and, in some instances, restore signaling.…”

Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu1 Receptors Found in Schizophrenics

“…However, as the only mGu 1 PAM tool compound with CNS exposure, the field had no other option than to employ the lone existing tool to validate and understand the receptor’s role in numerous CNS disorders. 17–20 Thus, to provide an mGlu 1 PAM in vivo tool compound with a more desired profile ( F u > 3%, K p > 0.8, clean CYP profiles) to ensure robust target engagement and validation, as well as a distinct chemotype to avoid chemo-type-related pharmacology, our lab has recently focused on the development of next generation mGlu 1 PAMs and ago-PAMs.…”

Modulation, Plasticity and Pathophysiology of the Parallel Fiber-Purkinje Cell Synapse

“…In this model, silencing the SCA1 transgene restored both mGlu 1 receptor expression and motor function, suggesting a causative role of this signaling pathway in ataxic symptoms (Zu et al, 2004). The reduction in the expression of mGlu 1 receptor mRNA and protein levels in a SCA1-model mouse with severe ataxia was confirmed by Notartomaso et al (2013). Treatment of these mice with a positive allosteric modulator of the mGlu 1 receptor caused a long-lasting improvement of motor performance (Notartomaso et al, 2013).…”

“…The reduction in the expression of mGlu 1 receptor mRNA and protein levels in a SCA1-model mouse with severe ataxia was confirmed by Notartomaso et al (2013). Treatment of these mice with a positive allosteric modulator of the mGlu 1 receptor caused a long-lasting improvement of motor performance (Notartomaso et al, 2013). However, in these studies, the mGlu 1 -EPSC was not assessed, so that the role of mGlu 1 -mediated synaptic signaling at the PF-PC synapse remains uncertain.…”