Muscarinic Receptor Modulator Shows Promise in Rett Mouse Model | M1 Receptors Found to Improve Behavior, Ease Respiratory Symptoms

A so-called positive allosteric modulator aimed at increasing activity at a subset of muscarinic acetylcholine receptors (mAChRs) — called M1 receptors — improved behavior and eased respiratory symptoms in a mouse model of Rett syndrome, a study found.

The beneficial effects of the compound, dubbed VU595, could in part be due to its ability to restore more normal gene expression (activity) levels in the brain, data suggested.

“Together, these data suggest that M1 [positive allosteric modulators] could represent a new class of RTT [Rett] therapeutics,” the researchers wrote.

the study,”Clinical and Preclinical Evidence for M1 Muscarinic Acetylcholine Receptor Potentiation as a Therapeutic Approach for Rett Syndrome,” was published in the journal Neurotherapeutics.

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Rett symptoms are mainly caused by genetic mutations leading to the disrupted function of the MECP2 protein. Because MECP2 is normally involved in regulating the activity of many other genes — particularly those in the brain — its disruption leads to global changes in gene activity and severe disturbances in the brain, heart, and respiratory function.

Acetylcholine’s role in Rett

Acetylcholine is a chemical messenger which exerts numerous functions in the brain, including the regulation of memory and breathing. Studies have shown that the activity of the enzyme responsible for producing acetylcholine is diminished in Rett patients, and increasing data in animal studies implicate low acetylcholine in the disease biology of Rett.

A research team previously found that the production of several subtypes of mAChRs — receptors on which acetylcholine acts to exert its effects — was lower in tissue samples taken from Rett patients compared with age-matched tissue from healthy people (controls).

Taken together, the data suggest that therapies aimed at increasing the activity at MAChRs — effectively increasing the signaling pathways normally activated by acetylcholine — could be a therapeutic approach for Rett.

To explore this possibility, the same team of scientists now examined the levels of mAChR subtypes in a larger group of postmortem brain samples from 40 Rett patients and 12 age-matched control samples. While multiple mAChR subtypes were lower in the Rett samples, decreases in a particular one called M1, were also linked to lower MeCP2 activity levels.

In a mouse model of Rett, a similar decrease in M1 was observed in a brain region called the brainstem, which regulates subconscious body functions, like breathing and heart rate.

The findings raised the possibility that enhancing the activity of M1 receptors might have therapeutic benefits in Rett, the researchers said. To test their hypothesis, the scientists injected VU595, an M1 positive allosteric modulator, into some Rett mice, while others received a vehicle injection with no treatment.

A positive allosteric modulator is a type of compound designed to enhance the normal activity at a receptor. In other words, Vu595 helps to amplify acetylcholine’s effects on M1 receptors.

A battery of behavioral tests designed to evaluate classic Rett symptoms showed that some aspects of behavior were significantly improved after VU595 treatment. Specifically, VU595 rescued deficits in social behavior, spatial memory, and associative memory — the ability to learn and remember relationships between two things.

The treatment also led to significant benefits in respiratory symptoms, leading to fewer apneas — when breathing repeatedly stops and starts during sleep — than in vehicle-given mice. The researchers found that these effects related to Vu595’s ability to facilitate the transition between inhaling and exhaling.

Given MECP2’s role in regulating gene expression, the team examined brain tissue from two brain regions — hippocampus and brainstem — of the Rett mice to investigate whether VU595 treatment could restore more normal global gene expression.

“The brainstem and hippocampus were chosen because they represent regions of the brain associated with apneas and cognition, where M1 PAM [positive allosteric modulators] efficacy was observed,” the scientists wrote.

Results showed that among 2,141 genes that were disrupted in the brainstem in the vehicle group (relative to control samples with normal Mecp2), 1,384 of them – 67.4% – were no longer disrupted with VU595 treatment. Similarly, among 2,727 genes disrupted in the hippocampus of Rett mice, 2,294, or 84.1%, were no longer affected after treatment.

Notably, modulation of M1 receptors appeared to inhibit a protein called GSK3-beta and increased the presence of NMDA receptors, both of which have been previously shown to influence Rett symptoms in mouse models. The team noted that the mechanisms underlying the effects of these pathways in Rett warrant further investigation.

“Together, these data advocates for continued development and optimization of M1 [positive allosteric modulators] for [Rett]as well as for related autism-associated disorders with overlapping pathologies,” the researchers concluded.

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