Mecp2 Deficiency in Peripheral Sensory Neuron Improves Cognitive Function by Enhancing Hippocampal Dendritic Spine...

Methyl-CpG-binding protein 2 (Mecp2) is an epigenetic modulator and numerous studies have explored its impact on the central nervous system manifestations. However, little attention has been given to its potential contributions to the peripheral nervous system (PNS). To investigate the regulation of Mecp2 in the PNS on specific central regions, we generated Mecp2 mice with the sensory-neuron-specific deletion of the Mecp2 gene and found the mutant mice had a heightened sensitivity to temperature, which, however, did not affect the sense of motion, social behaviors, and anxiety-like behavior. Notably, in comparison to Mecp2 mice, Mecp2 mice exhibited improved learning and memory abilities. The levels of hippocampal synaptophysin and PSD95 proteins were higher in Mecp2 mice than in Mecp2 mice. Golgi staining revealed a significant increase in total spine density, and dendritic arborization in the hippocampal pyramidal neurons of Mecp2 mice compared to Mecp2 mice. In addition, the activation of the BDNF-TrkB-CREB1 pathway was observed in the hippocampus and spinal cord of Mecp2 mice. Intriguingly, the hippocampal BDNF/CREB1 signaling pathway in mutant mice was initiated within 5 days after birth. Our findings suggest a potential therapeutic strategy targeting the BDNF-TrkB-CREB1 signaling pathway and peripheral somasensory neurons to treat learning and cognitive deficits associated with Mecp2 disorders.