MeCP2 deficiency impairs motor cortical circuit flexibility associated with motor learning

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Rett syndrome (RTT) is a postnatal neurological disorder caused by loss-of-function mutations in the MECP2 gene.
• Motor dysfunction is a primary clinical manifestation of RTT, appearing early in the disease course.
• Mecp2-null mouse models exhibit phenotypes mirroring human RTT, including progressive motor deficits.

Purpose of the Study:

• To investigate circuit-level functional changes in the motor cortex during the progression of motor deficits in Mecp2-null mice.
• To identify potential circuit-based biomarkers for motor regression in RTT.

Main Methods:

• Electrophysiological recordings of motor cortical neuron populations during locomotion in Mecp2-null and wild-type mice on a motorized wheel-treadmill.
• Analysis of neuronal firing activity, selectivity (running/rest), and population activity synchronization in relation to locomotion speed and training.

Main Results:

• Wild-type mice showed a decrease in running-selective neurons and increased population activity synchronization with training.
• Mecp2-null mice exhibited a stable proportion of running-selective neurons, an elevated and increasing fraction of rest-selective neurons with motor decline, and a lack of population activity synchronization.
• These distinct neural activity patterns were observed across all functional cell types during locomotion.

Conclusions:

• Mecp2 deficiency disrupts the normal adaptation of motor cortex neural circuits during locomotion and training.
• Altered neuronal selectivity and lack of population synchronization in Mecp2-null mice represent potential circuit-level biomarkers for motor regression in Rett syndrome.