Loss of Mecp2 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 (MECP2). 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 Mecp2 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 Mecp2 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 Mecp2 KO mice. Finally, we find similar abnormalities of PV networks plasticity in symptomatic female Mecp2 heterozygous mice. These results indicate that in Mecp2 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.

Significance Statement Understanding the pathological processes impacting somatosensory processing and motor control represents a major challenge for clinical management of individuals affected by Rett syndrome. We found that Mecp2 is important, starting from young age, for the correct molecular and synaptic organization of parvalbumin-positive interneurons in cortical areas responsible for sensory-motor skills. Intriguingly, even partial Mecp2 loss produces an atypical upregulation of parvalbumin expression in these cells that correlates with the severity of motor behavioral impairments and is associated with defective cortical activity in KO mice. Because in behaviorally impaired Mecp2 KO mice excessive activity-dependent excitatory connectivity is established with these interneurons, our study suggests that partial inhibition of parvalbumin-positive cells would be beneficial for motor impairments in Rett syndrome.