Reduced complexity of brain and behavior due to MeCP2 disruption and excessive inhibition

Abstract

Rett syndrome (RTT) is a devastating neurodevelopmental disorder, caused by disruptions to the MECP2 gene, and resulting in severe cognitive and motor impairment. Previous work strongly suggests that healthy MECP2 function is required to have a normal balance between excitatory and inhibitory neurons. However, the details of how neural circuit dynamics and motor function are disrupted remain unclear. How might imbalanced E/I cause problems for motor function in RTT? We addressed this question in the motor cortex of awake, freely behaving rats, comparing normal rats with a transgenic rat model of RTT. We recorded single-unit spiking activity while simultaneously recording body movement of the rats. We found that RTT rats tend to have excessive synchrony among neurons in the motor cortex and less complex body movements. Importantly, greater synchrony was correlated with greater stereotypy of relationships between neurons and body movements. To further test how our observations were related to an E/I imbalance, we pharmacologically altered inhibitory synaptic interactions. We were able to recapitulate many of the phenomena we found in MECP2-deficient rats by enhancing inhibition in normal rats. Our results suggest that RTT-related E/I imbalance in the motor cortex gives rise to excessive synchrony and, consequently, a stereotyped motor code, which may underlie abnormal motor function in RTT.