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Rett syndrome is a neurodevelopmental disorder that that affects 1 in every 10,000 female births. The goal of this project is to determine whether a temporal divergence in excitatory neuronal circuitry exists in Rett syndrome that could place patients at risk for adverse effects when using therapeutics designed to alter glutamatergic transmission. In the clinic, young Rett patients undergo a period of rapid developmental regression, which eventually plateaus in an impaired state for many years. However, as disease progresses, older Rett patients experience the gradual presentation of a Parkinsonian phenotype. This biphasic presentation indicates that multiple mechanisms may govern disease progression, some early and acute, and others more chronic in nature. Patient and animal studies indicate that excitotoxicity during postnatal synaptogenesis may underlie acute phases of the disease, but that this transitions into hypofunction of excitatory circuits later in life. Therapeutically, these findings create a paradox, as drugs designed to amplify glutamatergic tone late in disease could inadvertently harm patients if given too early. These studies will test the hypothesis that highly selective mGlu5 positive allosteric modulators (PAMs) will reduce symptom severity in Rett mice by potentiating excitatory signals when administered in advanced disease states, but will worsen disease progression when administered during postnatal synaptogenesis by enhancing excitotoxicity. To address this, distinct groups of Mecp2-/y mice will be dosed with the mGlu5 PAM VU0462807 specifically during synaptogenesis and late in disease progression. In support of a late stage benefit, the investigators have already observed that VU0462807 induces a dramatic reversal of Rett phenotypes in post-symptomatic Mecp2-/y mice. Additionally, during synaptogenesis, a separate group of Mecp2-/y mice will be dosed with the mGlu5 antagonist MTEP to determine if tempering excitotoxicity during only that critical developmental window will affect a long-term phenotypic benefit. Phenotypic analysis will encompass the social and motor aspects of Rett syndrome, while molecular analysis will encompass common Rett pathologies and synaptologies. This project will define the potential of mGlu5 PAMs as Rett syndrome therapeutics and, more broadly, provide valuable information regarding the interplay between disease progression and mechanism of therapeutic intervention.