Longitudinal analysis in Mecp2-het female mice reveals atypical nociceptive behaviours.

Rett Syndrome (RTT), a neurodevelopmental disorder predominantly affecting females, is characterised by evolving symptoms impacting motor and sensory domains. Herein, we present a study of longitudinal analyses, from 2- to 6-month of age, of Mecp2 heterozygous (Mecp2-het) female mice to comprehensively explore pain perception in RTT. Interestingly, we found a significant variability in the timing and progression of symptom onset among Mecp2-het females, with individuals classified as either early- or late-symptomatic based on the emergence of hallmark neurological features such as clasping and gait abnormalities. This variability pinpoints the heterogeneity of the disease model and highlights the need to stratify Mecp2-het females by symptom onset in future studies to account for the diverse trajectories of disease progression. Additionally, our results reveal a shift from presymptomatic hypersensitivity in the von Frey test to apparent hyposensitivity, intricately linked with the onset of motor symptoms. Further, we found decreased neuronal activation in 6-month-old Mecp2-het females after the hot plate test in the periaqueductal grey, as measured by cFos expression, which does not happen with younger presymptomatic Mecp2-het females. Similarly, there is a lower expression of cannabinoid receptor 1 (CB1) in this area when compared to wild-type siblings. Taken together, our results suggest that both motor impairment and a possible dysregulation of endogenous analgesia might contribute to aberrant sensitivity in Mecp2-het mice. Our study emphasises the presymptomatic phase as crucial for understanding sensory abnormalities in Mecp2-het mice and highlights the challenges in identifying pain in RTT patients. KEY MESSAGES: Mecp2-het mice show early hypersensitivity to stimuli that shifts with age. Classification of Mecp2-het mice by symptom onset shows phenotypic variety. Mecp2-het mice show lower PAG activity when facing a thermal stimulus. Mecp2-het mice show decreased activity and CB1 receptor levels in the PAG.