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

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)–CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu7) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations in MECP2 reduce mGlu7 protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models. In rodents, this reduction impairs mGlu7-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu7 activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu7 positive allosteric modulation decreases apneas in Mecp2+/− mice, suggesting that mGlu7 may be a potential therapeutic target for multiple aspects of the RTT phenotype.

Total RNA Sequencing of Rett Syndrome Autopsy Samples Identifies the M4 Muscarinic Receptor as a Novel Therapeutic Target

“…Motor Cortex and Cerebellum RNA Sequencing. We recently obtained six cerebellum samples from RTT patient autopsies to serve as a complement to our existing work in the motor cortex, as well as eight age, sex, and PMI matched controls [described further in Gogliotti et al (2016Gogliotti et al ( , 2017 and Supplemental Table 1]. As a baseline characterization of these new samples, we quantified MeCP2, mGlu 5 , and mGlu 7 protein expression and observed it to be significantly reduced in a manner similar to what we previously reported in the motor cortex (Supplemental Fig.…”

“…Recently, we obtained a set of RTT samples from the motor cortex of RTT patients in sufficient quantity to conduct RNA and protein analysis. These samples were previously used to profile the translational relevance of the preclinical target genes GRM5 (mGlu 5 ) (Gogliotti et al, 2016) and GRM7 (mGlu 7 ) (Gogliotti et al, 2017). Building on these data sets, we next asked the question of whether novel genes or pathways could be identified using transcriptomics.…”

Phenotypic profiling of mGlu7 knockout mice reveals new implications for neurodevelopmental disorders

“…We recently reported preclinical efficacy of mGlu 7 potentiation in a RTT mouse model. 16 One limitation of our previous work was the use of a nonselective compound that potentiates the activity of all group III mGlu receptors. The phenotypes reported here overlap extensively with those reported in RTT models (reviewed in 61), providing further support for mGlu 7 as a bona fide therapeutic target for RTT.…”

“…11 Additionally, singlenucleotide polymorphisms have been associated with increased risk for ASD, ADHD and schizophrenia. [12][13][14][15] We recently reported that mGlu 7 protein expression was significantly reduced in autopsy samples from patients with Rett syndrome (RTT), 16 suggesting that altered mGlu 7 expression can be a feature of monogenetic disorders in which the causative gene is not GRM7. In a mouse model of RTT, we found that potentiation of mGlu 7 activity with an allosteric modulator improved disease phenotypes.…”

“…In a mouse model of RTT, we found that potentiation of mGlu 7 activity with an allosteric modulator improved disease phenotypes. 16 This shows that mGlu 7 could be a feasible target for therapeutic intervention; however, these previous studies relied on a combination of nonselective compounds because a truly selective activator or positive allosteric modulator for mGlu 7 is not yet available. Therefore, more work is needed to validate mGlu 7 as a therapeutic target in RTT and to evaluate whether mGlu 7 potentiation can also provide benefit in other models of neurodevelopmental disorders.…”