Abstract
Rett Syndrome is a devastating neurodevelopmental disorder resulting from mutations in the gene MECP2. Mutations of Mecp2 that are restricted to GABAergic cell types largely replicate the behavioral phenotypes associated with mouse models of Rett Syndrome, suggesting a pathophysiological role for inhibitory interneurons. Recent work has suggested that vasoactive intestinal peptide-expressing (VIP) interneurons may play a critical role in the proper development and function of cortical circuits, making them a potential key point of vulnerability in neurodevelopmental disorders. However, little is known about the role of VIP interneurons in Rett Syndrome. Here we find that loss of MeCP2 specifically from VIP interneurons replicates key neural and behavioral phenotypes observed following global Mecp2 loss of function.
Highlights
Single-unit recordings revealed that loss of MeCP2 in the Dlx5/6 mutants led to a three-fold increase in the firing rates of regular-spiking, putative excitatory pyramidal neurons as compared to that in control animals (p=0.004), and this finding was replicated in the vasoactive intestinal peptide-expressing (VIP) (p=0.03) and somatostatin-expressing interneurons (SST) (p=0.002; Kruskal-Wallis test with Dunn’s post-test) mutants (Figure 2E)
Our results reveal an unanticipated role for VIP interneurons in the Mecp2 loss-of-function model of Rett Syndrome
We found that Mecp2 deletion from VIP interneurons recapitulates major phenotypes observed following pan-interneuron Mecp2 deletion at the levels of both neural activity and behavior (Supplementary file 1)
Summary
To confirm that MeCP2 is expressed in three major populations of GABAergic interneurons, we costained sections of cortex from adult mice with antibodies for interneuron markers and MeCP2 (Figure 1, Figure 1—figure supplement 1). MeCP2 depletion from specific interneuron populations had markedly different effects on seizure incidence (Figure 1—figure supplement 2A-B). The mean age of initial seizure was significantly earlier in Mecp2–/y mutants, but not the Dlx5/6, PV, SST, or VIP mutants, compared to Mecp2f/y controls (Figure 1—figure supplement 2B). MeCP2 depletion caused a modest change in LFP power, measured during periods of quiescence, in the 3– 6 Hz range in the Dlx5/6 mutants (p=0.03; Kruskal-Wallis test with Dunn’s post-test), but not in other groups (Figure 2C). Hippocampal recordings revealed a loss of gamma-range LFP power in the Dlx5/6 mutants that was replicated by the SST mutants (Figure 2—figure supplement 2), suggesting potentially distinct celltype-specific roles in different brain areas
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