Date of Award

Fall 8-22-2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology and Experimental Therapeutics

First Advisor

Rocco Gogliotti

Abstract

Rett syndrome (RTT) is a rare neurodevelopmental disorder caused by mutations in the gene coding for methyl-CpG binding protein 2 (MeCP2). Currently, there is no cure for RTT and few effective treatment options to address the social, cognitive, motor, and respiratory symptoms that patients face. With the goal of identifying novel targets, our lab performed RNA-sequencing experiments in human autopsy samples and found decreased levels of the M1 muscarinic acetylcholine receptor. We have established that potentiation of this receptor in a Mecp2+/- mouse model of RTT rescues social, cognitive, and respiratory phenotypes, providing support for using drugs that act on M1 for RTT. The efficacy of this compound was linked to the Gsk3β and NMDA receptor signaling axis, which others have targeted and found to be therapeutic in RTT. While these results were exciting, different mutations in MeCP2 confer distinct transcriptional disruptions and we next addressed the possibility that not all RTT patient subpopulations would have decreased M1. When M1 expression was binned by MeCP2 mutation, it was found that patients with the common R168X and R270X mutations had decreased expression, while those with R255X, R306C, and T158M mutations did not. This raises the question of whether target disruption is needed for the efficacy of drugs that act on the M1 receptor. This potential challenge was addressed by efficacy testing of the M1 positive allosteric modulator (PAM) VU595 in Mecp2+/R168X, Mepc2+/T158M, and Mecp2+/R306C mouse models. Our results established a relationship between low M1 expression and compound efficacy of VU595 in RTT. While VU595 has demonstrated efficacy, the population of neurons driving its therapeutic effects is unclear. Using whole-brain light sheet imaging, we found that c-Fos expression is increased throughout the brain in Mecp2+/- mice but is normalized after VU595 administration. Data from this experiment suggests that excitatory projections from fore-and midbrain regions project to and activate inhibitory neurons in the brainstem to exert a cooling effect on neuronal activity. These experiments further advocate for the development of muscarinic PAMs for RTT by identifying the brain regions and patient populations where they are most likely to be effective.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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