mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome

• Published in: Human molecular genetics Vol. 25; no. 10; pp. 1990 - 2004
• Main Authors: Gogliotti, Rocco G, Senter, Rebecca K, Rook, Jerri M, Ghoshal, Ayan, Zamorano, Rocio, Malosh, Chrysa, Stauffer, Shaun R, Bridges, Thomas M, Bartolome, Jose M, Daniels, J Scott, Jones, Carrie K, Lindsley, Craig W, Conn, P Jeffrey, Niswender, Colleen M
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15.05.2016
• Subjects: Adult; Allosteric Regulation - genetics; Animals; Autistic Disorder - drug therapy; Autistic Disorder - genetics; Autistic Disorder - pathology; Autopsy; Disease Models, Animal; Female; Gene Expression Regulation - drug effects; Hippocampus - drug effects; Hippocampus - pathology; Humans; Male; Methyl-CpG-Binding Protein 2 - genetics; Mice; Mice, Knockout; Motor Cortex - drug effects; Motor Cortex - pathology; Neuronal Plasticity - drug effects; Pyrazoles - administration & dosage; Pyrimidinones - administration & dosage; Receptor, Metabotropic Glutamate 5 - biosynthesis; Receptor, Metabotropic Glutamate 5 - genetics; Rett Syndrome - drug therapy; Rett Syndrome - genetics; Rett Syndrome - pathology; Seizures - drug therapy; Seizures - genetics; Seizures - pathology; Signal Transduction - drug effects; Young Adult
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddw074

Rett syndrome (RS) is a neurodevelopmental disorder that shares many symptomatic and pathological commonalities with idiopathic autism. Alterations in protein synthesis-dependent synaptic plasticity (PSDSP) are a hallmark of a number of syndromic forms of autism; in the present work, we explore the consequences of disruption and rescue of PSDSP in a mouse model of RS. We report that expression of a key regulator of synaptic protein synthesis, the metabotropic glutamate receptor 5 (mGlu ) protein, is significantly reduced in both the brains of RS model mice and in the motor cortex of human RS autopsy samples. Furthermore, we demonstrate that reduced mGlu expression correlates with attenuated DHPG-induced long-term depression in the hippocampus of RS model mice, and that administration of a novel mGlu positive allosteric modulator (PAM), termed VU0462807, can rescue synaptic plasticity defects. Additionally, treatment of Mecp2-deficient mice with VU0462807 improves motor performance (open-field behavior and gait dynamics), corrects repetitive clasping behavior, as well as normalizes cued fear-conditioning defects. Importantly, due to the rationale drug discovery approach used in its development, our novel mGlu PAM improves RS phenotypes and synaptic plasticity defects without evoking the overt adverse effects commonly associated with potentiation of mGlu signaling (i.e. seizures), or affecting cardiorespiratory defects in RS model mice. These findings provide strong support for the continued development of mGlu PAMs as potential therapeutic agents for use in RS, and, more broadly, for utility in idiopathic autism.