Profiling metabotropic glutamate receptor 7 expression in Rett syndrome: consequences for pharmacotherapy

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene.
• Patients exhibit developmental regression, seizures, and autistic features.
• Previous work showed decreased metabotropic glutamate receptor 7 (mGlu7) in RTT brains and efficacy of mGlu7 positive allosteric modulators (PAMs) in mouse models.

Purpose of the Study:

• To investigate mGlu7 expression across a broader range of RTT patient mutations.
• To evaluate the expression of other group III mGlu receptors (mGlu4, mGlu8) in RTT.
• To determine if mGlu7 PAMs can reduce respiratory deficits in mouse models with specific MECP2 mutations.

Main Methods:

• Analyzed mRNA expression of mGlu4, mGlu7, and mGlu8 in a larger cohort of RTT patient brain samples.
• Correlated mGlu receptor expression with MECP2 mutation severity.
• Administered the mGlu7 PAM VU0422288 to Mecp2(R306C/+) mice to assess effects on apneas.

Main Results:

• Significant decreases in mGlu7 mRNA expression were observed in RTT patients, particularly those with severe MECP2 mutations.
• No significant changes in mGlu4 or mGlu8 mRNA expression were found.
• A novel correlation between mGlu4 and mGlu8 expression was identified in human brain samples.
• Administration of the mGlu7 PAM VU0422288 significantly reduced apneas in mice modeling a mild MECP2 mutation.

Conclusions:

• Reduced mGlu7 expression is a feature of RTT, especially in severe cases.
• mGlu7 PAMs demonstrate potential for treating respiratory symptoms across the RTT spectrum.
• Further research into mGlu7 modulation may offer therapeutic strategies for RTT.