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

Gogliotti RG, Senter RK, Rook JM, Ghoshal A, Zamorano R, Malosh C, Stauffer SR, Bridges TM, Bartolome JM, Daniels JS, Jones CK, Lindsley CW, Conn PJ, Niswender CM
Hum Mol Genet. 2016 25 (10): 1990-2004

PMID: 26936821 · PMCID: PMC5062588 · 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.

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MeSH Terms (23)

Adult Allosteric Regulation Animals Autistic Disorder Autopsy Disease Models, Animal Female Gene Expression Regulation Hippocampus Humans Male Methyl-CpG-Binding Protein 2 Mice Mice, Knockout Motor Cortex Neuronal Plasticity Pyrazoles Pyrimidinones Receptor, Metabotropic Glutamate 5 Rett Syndrome Seizures Signal Transduction Young Adult

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