The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease

Abstract

Huntington's Disease (HD) is an autosomal-dominant neurodegenerative disorder, characterized by involuntary body movements, cognitive impairment, and psychiatric disorder. The metabotropic glutamate receptor 5 (mGluR5) plays an important role in HD and we have recently demonstrated that mGluR5-positive allosteric modulators (PAMs) can ameliorate pathology and the phenotypic signs of a mouse model of HD. In this study, we investigated the molecular mechanisms involved in mGluR5 PAMs effect on memory. Our results demonstrate that subchronic treatment with the mGluR5 PAM VU0409551 was effective in reversing the memory deficits exhibited by BACHD mice, a mouse model for HD. Moreover, VU0409551 treatment stabilized mGluR5 at the cellular plasma membrane of BACHD mice, increasing the expression of several genes important for synaptic plasticity, including c-Fos, brain-derived neurotrophic factor, Arc/Arg3.1, syntaxin 1A, and post-synaptic density-95. In addition, VU0409551 treatment also increased dendritic spine density and maturation and augmented the number of pre-synaptic sites. In conclusion, our results demonstrate that VU0409551 triggered the activation of cell signaling pathways important for synaptic plasticity, enhancing the level of dendritic spine maturation and rescuing BACHD memory impairment. OPEN PRACTICES: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.

mGluR5 regulates REST/NRSF signaling through N-cadherin/β-catenin complex in Huntington’s disease

“…Several previous studies demonstrated the importance of mGluR5 in the pathophysiology of HD [ 18 – 21 ]. Moreover, mGluR5 was shown to modulate cadherin/β-catenin association in the vascular endothelium [ 17 ].…”

In-depth characterization of congenital Zika syndrome in immunocompetent mice: Antibody-dependent enhancement and an antiviral peptide therapy

“…For immunostaining analyses, brain samples were processed and sliced as previously described [17]. Slices of cortex were stained for microglia (Iba-1 staining), neurons (NeuN staining), and astrocytes (S100β staining) following procedures supplied by the manufacturer (Vector Elite kit, Vector Laboratories, USA).…”

International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors

“…Beyond neurologic and psychiatric disorders, inhibition of mGlu 1 receptors is neuroprotective (in vitro and in vivo) after oxygen-glucose deprivation or ischemic insult (Henrich-Noack et al, 1998;Pellegrini-Giampietro et al, 1999) and may therefore offer a novel intervention for stroke. For multiple preclinical models of neurodegenerative diseases, genetic ablation or pharmacological inhibition of mGlu 5 receptors is neuroprotective and treats associated symptoms, for example, acting procognitively in Alzheimer's disease or Huntington's disease (reviewed in Ribeiro et al, 2017) or improving motor deficits in amyotrophic lateral sclerosis (reviewed in Battaglia and Bruno, 2018) or Parkinson's disease (Mazur, 1995;Battaglia et al, 2004;Armentero et al, 2006;Ambrosi et al, 2010;Black et al, 2010;Masilamoni et al, 2011;Fuzzati-Armentero et al, 2015), although mGlu 5 receptor activators/potentiators may also treat cognitive symptoms associated with Huntington's disease (Doria et al, 2013(Doria et al, , 2015(Doria et al, , 2018. Inhibition of mGlu 5 receptors is also indicated for treating neurodegeneration associated with drugs of abuse (Battaglia et al, 2002).…”