Loss of <i>Mecp2</i> Causes Atypical Synaptic and Molecular Plasticity of Parvalbumin-Expressing Interneurons Reflecting Rett Syndrome–Like Sensorimotor Defects

Abstract

Rett syndrome (RTT) is caused in most cases by loss-of-function mutations in the X-linked gene encoding methyl CpG-binding protein 2 (<i>MECP2</i>). Understanding the pathological processes impacting sensory-motor control represents a major challenge for clinical management of individuals affected by RTT, but the underlying molecular and neuronal modifications remain unclear. We find that symptomatic male <i>Mecp2</i> knockout (KO) mice show atypically elevated parvalbumin (PV) expression in both somatosensory (S1) and motor (M1) cortices together with excessive excitatory inputs converging onto PV-expressing interneurons (INs). In accordance, high-speed voltage-sensitive dye imaging shows reduced amplitude and spatial spread of synaptically induced neuronal depolarizations in S1 of <i>Mecp2</i> KO mice. Moreover, motor learning-dependent changes of PV expression and structural synaptic plasticity typically occurring on PV⁺ INs in M1 are impaired in symptomatic <i>Mecp2</i> KO mice. Finally, we find similar abnormalities of PV networks plasticity in symptomatic female <i>Mecp2</i> heterozygous mice. These results indicate that in <i>Mecp2</i> mutant mice the configuration of PV⁺ INs network is shifted toward an atypical plasticity state in relevant cortical areas compatible with the sensory-motor dysfunctions characteristics of RTT.