Targeting mGlu1 Receptors in the Treatment of Motor and Cognitive Dysfunctions in Mice Modeling Type 1 Spinocerebellar Ataxia

Abstract

Type 1 spinocerebellar ataxia (SCA1) is a progressive neurodegenerative disorder with no effective treatment to date. Using mice modeling SCA1, it has been demonstrated that a drug that amplifies mGlu1 receptor activation (mGlu1 receptor PAM, Ro0711401) improves motor coordination without the development of tolerance when cerebellar dysfunction manifests (i.e., in 30-week-old heterozygous ataxin-1 [154Q/2Q] transgenic mice). SCA1 is also associated with cognitive dysfunction, which may precede cerebellar motor signs. Here, we report that otherwise healthy, 8-week-old SCA1 mice showed a defect in spatial learning and memory associated with reduced protein levels of mGlu1α receptors, the GluN2B subunit of NMDA receptors, and cannabinoid CB1 receptors in the hippocampus. Systemic treatment with Ro0711401 (10 mg/kg, s.c.) partially corrected the learning deficit in the Morris water maze and restored memory retention in the SCA1 mice model. This treatment also enhanced hippocampal levels of the endocannabinoid, anandamide, without changing the levels of 2-arachidonylglycerol. These findings suggest that mGlu1 receptor PAMs may be beneficial in the treatment of motor and nonmotor signs associated with SCA1 and encourage further studies in animal models of SCA1 and other types of SCAs.

Therapeutic Strategies for Spinocerebellar Ataxia Type 1

“…Next to the potassium channel dysfunction, contributing to alterations in the PC intrinsic activity, altered excitatory glutamatergic inputs, linked to the type-1 metabotropic glutamate receptors (mGluR1), also contribute to the altered PC activity observed in SCA1 (Figure 3, [91][92][93]). Reductions in mGluR1 mRNA levels as well protein levels have been observed in symptomatic elderly SCA1 154Q/2Q mice [91,94]. Furthermore, in pre-symptomatic B05 transgenic mice, reduced mGluR-excitatory postsynaptic current (EPSC) amplitudes were observed, leading to altered PC activity and eventually to PC death [93].…”

“…The observed reduction in mGluR1-mediated EPSC amplitude can be modulated by so-called positive allosteric modulators (PAMs), which amplify the mGluR1 receptor function [91,94,95]. Subcutaneous injection of SCA1 154Q/2Q mice with the Ro0711401 PAM led to a significant increase in motor performance after 30 min [91].…”

“…This could be explained by the induction of cerebellar long-term depression during the repeated execution of the rotarod assay, which could possibly induce a form of procedural memory [91]. Additionally, defects in learning and memory were improved [94]. On the other hand, intraperitoneal injection of the JNJ16259685 negative allosteric modulator (NAM) in SCA1 154Q/2Q mice resulted in markedly reduced motor function [91].…”