Brain activity may be biomarker for Rett treatment response
Measuring sound-driven response could be useful, study finds
Changes in auditory event-related potentials, or AEPs, the brain’s electrical activity in response to sound, may serve as a non-invasive biomarker to assess treatment response in people with Rett syndrome, a study suggested.
Depressed AEPs, as measured by electroencephalography (EEG), which detects the brain’s electrical activity, were normalized when Rett mice were treated with a molecule that improved multiple features of Rett, the data showed.
“These findings suggest that neurophysiological features, like AEP, have potential as sensitive and quantitative biomarkers that may be useful in evaluating … pharmacological interventions as novel [Rett] treatment strategies,” the researchers wrote.
The study, “Potentiation of group III metabotropic glutamate receptors positively affects neurophysiological features in a mouse model of RTT syndrome,” was published in the Journal of Pharmacology and Experimental Therapeutics.
In most Rett cases, mutations in the MECP2 gene disrupt the production of a protein with the same name that controls the activity of other genes. While the MeCP2 protein is present in most cells, it’s thought to help maintain connections between nerve cells by ensuring the right genes are active at the right time.
Brain disruption leads to symptoms
Because MeCP2 is particularly important for the brain’s development and function, its loss leads to impairments in language, coordination, and repetitive movements, alongside slower growth, difficulty walking, and seizures.
One key aspect of altered brain biology in Rett is abnormal signaling associated with the neurotransmitter glutamate, a chemical nerve cells use to communicate. Glutamate binds to and activates metabotropic glutamate receptors, or mGluRs, which, in turn, regulate the further release of neurotransmitters.
Researchers at Vanderbilt University discovered that the production of a mGluR called mGlu7 was reduced in a mouse model of Rett and in postmortem brain samples from Rett patients. Moreover, Rett mice treated with VU288, a molecule that activates mGlu7, showed improved learning, object recognition, social memory, and lung function, suggesting that mGlu7 may be a potential therapeutic target for multiple Rett features.
Building on these findings, the team investigated whether changes in AEPs, driven by VU288 as a model experimental treatment, can serve as biomarkers to support the development of new Rett therapies.
“Well-validated biomarkers that are sensitive to therapeutic intervention and treatment response that can be assessed in both preclinical models and affected individuals hold potential to accelerate [drug development],” the researchers wrote.
AEPs were evoked in mice using sound stimuli and measured by EEG. AEPs generate two prominent electrical activity peaks over time: N1, an initial downward peak thought to reflect early sound processing, and P2, a later upward peak believed to be part of sound recognition.
Before treatment, Rett mice showed significantly depressed AEP peak strengths (amplitudes) at N1 and P2 compared with healthy mice and a smaller difference between the N1 and P2 peaks. The P2 peak in Rett mice was also delayed (latent) and broader.
Rett mice treated with VU288 (30 mg/kg) boosted the AEP peak strengths, particularly N1 and the N1-P2 difference, but did not affect P2 peak delays. When normalized relative to untreated Rett mice, VU288-driven increases in N1 and N1-P2 matched those of healthy mice. In contrast, healthy mice treated with VU288 showed no changes in any AEP parameters.
Across three doses of VU288 (3, 10, and 30 mg/kg), the N1 peak rose by 1.5 to 1.9-fold, P2 by 1.5 to 1.9-fold, and N1-P2 by 1.4 to 1.7-fold. Significant increases were seen for N1 at 30 mg/kg, P2 at 10 mg/kg, and N1-P2 at 30 mg/kg. Again, no changes were observed in AEP peak delays.
When mice were treated with ADX88178, a molecule that activates other mGlu receptors but not mGlu7, no effect was observed for Rett mice, “suggesting that the target of [VU288] is likely mGlu7,” the team wrote.
Apart from changes in AEP peak strengths, treatment with VU288 had no impact on other EEG parameters, the reason for which was “unclear and may provide insight into the mechanistic underpinning of the abnormal neurophysiological features observed in [Rett] and the role of specific neurotransmitter systems,” the team wrote.
“The VU288 treatment effect in [Rett] mice was limited only to increases in AEP amplitude without any observable effect on other AEP or neurophysiological features,” the researchers wrote. Further studies are needed to “fully validate the utility of these features as biomarkers of treatment-response.”
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