MeCP2 gene therapy ameliorates disease phenotype in mouse model for Pitt Hopkins syndrome.

The neurodevelopmental disorder Pitt Hopkins syndrome (PTHS) causes clinical symptoms similar to Rett syndrome (RTT) patients. However, RTT is caused by MECP2 mutations whereas mutations in the TCF4 gene lead to PTHS. The mechanistic commonalities underling these two disorders are unknown, but their shared symptomology suggest that convergent pathway-level disruption likely exists.

Sex-dependent effects of carbohydrate source and quantity on caspase-1 activity in the mouse central nervous system.

Background: Mounting evidence links glucose intolerance and diabetes as aspects of metabolic dysregulation that are associated with an increased risk of developing dementia. Inflammation and inflammasome activation have emerged as a potential link between these disparate pathologies. As diet is a key factor in both the development of metabolic disorders and inflammation, we hypothesize that long term changes in dietary factors can influence nervous system function by regulating inflammasome activity and that this phenotype would be sex-dependent, as sex hormones are known to regulate metabolism and immune processes.

Potentiation of the M muscarinic acetylcholine receptor normalizes neuronal activation patterns and improves apnea severity in mice.

Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by loss-of-function mutations in the ( ) gene. RTT patients experience a myriad of debilitating symptoms, which include respiratory phenotypes that are often associated with lethality. Our previous work established that expression of the M muscarinic acetylcholine receptor (mAchR) is decreased in RTT autopsy samples, and that potentiation of the M receptor improves apneas in a mouse model of RTT; however, the population of neurons driving this rescue is unclear.

Optimized Administration of the M PAM VU0467154 Demonstrates Broad Efficacy, but Limited Effective Concentrations in Mice.

Hypofunction of cholinergic circuits and diminished cholinergic tone have been associated with the neurodevelopmental disorder Rett syndrome (RTT). Specifically, deletion of in cholinergic neurons evokes the same social and cognitive phenotypes in mice seen with global knockout, and decreased choline acetyltransferase activity and vesamicol binding have been reported in RTT autopsy samples. Further, we recently identified significant decreases in muscarinic acetylcholine receptor subtype 4 (M) expression in both the motor cortex and cerebellum of RTT patient autopsies and established proof of concept that an acute dose of the positive allosteric modulator (PAM) VU0467154 (VU154) rescued phenotypes in mice.