Loss of Mecp2 Causes Atypical Synaptic and Molecular Plasticity of Parvalbumin-Expressing Interneurons Reflecting Rett Syndrome-Like Sensorimotor Defects.

Noemi Morello,Riccardo Schina,Mary Phillips,Federica Pilotto,Lucas Pozzo-Miller,Riccardo Melani,Maurizio Giustetto,Ornella Plicato,Tommaso Pizzorusso

doi:10.1523/eneuro.0086-18.2018

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.

Highlights

Classic Rett syndrome (RTT) is a childhood neurologic disorder affecting ϳ1 in 10,000 live female births that results from loss-of-function mutations in the X-linked gene methyl CpG-binding protein 2 (MECP2), encoding a multifunctional protein that regulates gene expression and chromatin architecture by interacting with methylated nucleotides (Amir et al, 1999; Lyst and Bird, 2015)
Our results indicate that MeCP2 expression is required for correct synaptic remodeling that regulates the degree of PVϩ IN network plasticity in response to sensory-motor behavioral learning
We found for the first time that symptomatic Mecp2 KO mice show a robust shift of PVϩ IN networks in both S1 and M1 cortices toward high-PV expression configuration, a condition reflecting atypical plasticity of these INs (Donato et al, 2013)

Summary

Introduction

Classic Rett syndrome (RTT) is a childhood neurologic disorder affecting ϳ1 in 10,000 live female births that results from loss-of-function mutations in the X-linked gene MECP2 (methyl-CpG-binding protein 2), encoding a multifunctional protein that regulates gene expression and chromatin architecture by interacting with methylated nucleotides (Amir et al, 1999; Lyst and Bird, 2015). The clinical symptoms currently used as diagnostic criteria for RTT include an early neurologic regression, occurring after a period of typical development, that severely affects motor, cognitive, and communication skills (Smeets et al, 2012). Due to random X-chromosome inactivation, female Mecp heterozygous (Het) mice recapitulate the cellular mosaicism of Mecp expression found in RTT individuals and closely phenocopy the human condition, including the typical regression of acquired behavioral abilities (Katz et al, 2012; Samaco et al, 2013). Mecp is ubiquitously expressed, brain-specific deletion of Mecp in mice entirely recapitulates RTT-like phenotypes, suggesting that its function is most critical in brain cells (Chen et al, 2001; Guy et al, 2001). Recent studies revealed that loss of Mecp in specific neuronal subtypes leads to distinct RTT-like symptoms (Chao et al, 2010; Zhang et al, 2014), with GABAergic interneurons (INs) emerging as major players in RTT pathophysiology, espe-

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