mGlu₅positive 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 (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.

mGlu 7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome

“…Here, we describe how the loss of MECP2 results in decreased mGlu 7 signaling and demonstrate that potentiation of mGlu 7 function is sufficient to rescue synaptic plasticity deficits and improve multiple RTT-like phenotypes in mice. These data corroborate other studies suggesting that the pathophysiology of RTT is reversible in mouse models (12, 13, 33, 50). Finally, we have shown that mGlu 7 expression is sensitive to pathogenic mutations in MECP2 , and given that the full range of MECP2 -related disorders has only recently been appreciated, it is possible that mGlu 7 modulators will have broad utility that extends beyond RTT and into other disorders wherein MECP2 expression and function are compromised, such as MECP2 duplication syndrome and CDKL5 disorder (51, 52).…”

“…Total RNA was prepared from Mecp2 tm1.1bird ( Mecp2 − /y ) and Mecp2 +/y mice and the motor cortex of human samples as described in (12). The Life Technologies gene expression assays used were Grm4 (Mm01306128_m1), Grm7 (Mm0118924_m1), and Gad2 (Mm00484623_m1).…”

“…For human motor cortex protein preparation, frozen sections were obtained from the University of Maryland Brain and Tissue Bank, which is a Brain and Tissue Repository of the National Institutes of Health NeuroBioBank, and the Harvard Brain Tissue Resource Center, which is supported in part by Public Health Service contract HHSN-271-2013-00030C. Total protein was prepared as described in (12), and synaptosome preparations were prepared as described in (53). …”

“…Hence, several large-scale microarray studies have been performed to identify genes specifically regulated by MECP2 (10, 11). These studies, however, have failed to find gross changes in gene expression and have identified few targets regulated by MECP2 that are amenable to drug development (12, 13). …”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…However, these findings also raise the question of what signaling pathways and physiological responses are critical for specific in vivo actions of mGlu 5 PAMs. As new tools are further developed that selectively modulate specific signaling pathways by mGlu 5 , they will provide opportunities to develop a full understanding of the specific signaling pathways that are critical for mediating the efficacy of mGlu 5 PAMs in preclinical models of numerous CNS disorders including schizophrenia, fragile X syndrome, Rett syndrome, autistic spectrum disorders, obsessive compulsive disorder, Parkinson's disease, substance abuse (Ade et al, 2016; Gass et al, 2016; Gogliotti et al, 2016; Gould et al, 2016; Michalon et al, 2012; Rylander et al, 2010; Vicidomini et al, 2016), and others.…”