Developmental abnormalities of cortical interneurons precede symptoms onset in a mouse model of Rett syndrome

• Published in: Journal of neurochemistry 2014-10, Vol.131 (1), p.115-127
• Main Authors: Tomassy, Giulio Srubek, Morello, Noemi, Calcagno, Eleonora, Giustetto, Maurizio
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Brain; calretinin; Developmental disabilities; Disease Models, Animal; Female; GABAergic interneurons; Interneurons - metabolism; Interneurons - pathology; Male; Mecp2; Methyl-CpG-Binding Protein 2 - deficiency; Methyl-CpG-Binding Protein 2 - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; neocortex; Neurological disorders; Neurons; parvalbumin; Rett syndrome; Rett Syndrome - genetics; Rett Syndrome - metabolism; Rett Syndrome - pathology; Somatosensory Cortex - growth & development; Somatosensory Cortex - metabolism; Somatosensory Cortex - pathology
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12803

Rett syndrome (RTT, MIM312750), a neurodevelopmental disorder predominantly occurring in females, is caused in the majority of cases by sporadic mutations in the gene encoding the transcriptional modulator methyl‐CpG‐binding protein 2 (MECP2). In mice, impaired MeCP2 function results in severe motor, cognitive, and emotional defects. The lack of Mecp2 in γ‐aminobutyric acid‐(GABA) releasing forebrain interneurons (INs) recapitulate many RTT features, however, the role of this gene in the development of the cortical inhibitory system is still unknown. Here, we found that MeCP2 expression varies among the three major classes of cortical INs and its nuclear localization differs between neuronal types. The density of calretinin+ and parvalbumin+ INs increases in Mecp2 knockout mice (Mecp2−/y) already at early post‐natal developmental stages. In contrast, the density of somatostatin+ INs is not affected. We also found that the development of multipolar‐calretinin+ INs is selectively affected by the absence of Mecp2. Additionally, we show that in Mecp2 heterozygous female mice, a model closely mimicking human RTT condition, IN abnormalities are similar to those observed in Mecp2−/y mice. Together, our study indicates that loss of function of Mecp2 strongly interferes with the correct establishment of the neocortical inhibitory system producing effects that are specific to different IN subtypes. The neurological consequences of the Rett syndrome‐related Mecp2 gene mutation are still debated. We disclosed a novel cell‐specific role of MeCP2 in the organization of neocortical GABAergic interneurons assembly during post‐natal development of the mouse brain. Parvalbumin+ and calretinin+ interneurons being the mostly affected. Our data suggest new avenues for the development of biomarkers and therapeutic interventions for Rett syndrome. The neurological consequences of the Rett syndrome‐related Mecp2 gene mutation are still debated. We disclosed a novel cell‐specific role of MeCP2 in the organization of neocortical GABAergic interneurons assembly during post‐natal development of the mouse brain. Parvalbumin+ and calretinin+ interneurons being the mostly affected. Our data suggest new avenues for the development of biomarkers and therapeutic interventions for Rett syndrome.