title: mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome.
abstract: 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 (mGlu5) 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 mGlu5expression correlates with attenuated DHPG-induced long-term depression in the hippocampus of RS model mice, and that administration of a novel mGlu5positive 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 mGlu5PAM improves RS phenotypes and synaptic plasticity defects without evoking the overt adverse effects commonly associated with potentiation of mGlu5signaling (i.e. seizures), or affecting cardiorespiratory defects in RS model mice. These findings provide strong support for the continued development of mGlu5PAMs as potential therapeutic agents for use in RS, and, more broadly, for utility in idiopathic autism.
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Rocco G
authors.initials: RG
authors.lastname: Gogliotti
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Senter
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Jerri M
authors.initials: JM
authors.lastname: Rook
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Ayan
authors.initials: A
authors.lastname: Ghoshal
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Rocio
authors.initials: R
authors.lastname: Zamorano
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA, Department of Chemistry and.
authors.forename: Chrysa
authors.initials: C
authors.lastname: Malosh
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA, Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA and.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A., Toledo 45007, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Bartolome
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA, Department of Chemistry and.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA, Vanderbilt Kennedy Center.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA, Vanderbilt Kennedy Center, colleen.niswender@vanderbilt.edu.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
mesh_terms: D000328:Adult; D000494:Allosteric Regulation / Q000235:genetics; D000818:Animals; D001321:Autistic Disorder / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D001344:Autopsy; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009044:Motor Cortex / Q000187:drug effects / Q000473:pathology; D009473:Neuronal Plasticity / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D064529:Receptor, Metabotropic Glutamate 5 / Q000096:biosynthesis / Q000235:genetics*; D015518:Rett Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012640:Seizures / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: C000609687:1-(2-(phenoxymethyl)-6,7-dihydropyrazolo(1,5-a)pyrimidin-4(5H)-yl)ethanone; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D011720:Pyrazoles; D011744:Pyrimidinones; D064529:Receptor, Metabotropic Glutamate 5