MeCP2 and VIP-interneurons

A commonly used strategy in the dissection of the roles of autism risk genes is to delete them in particular cell types in a mouse. Previous attempts to do this with Mecp2, the gene mutated in the neurodevelopmental condition Rett syndrome, have identified important roles for the protein in interneurons. A new study goes further by deleting Mecp2 in specific subclasses of interneurons, revealing its critical role in vasoactive intestinal peptide (VIP)-expressing (VIP) cells.

Significant disruption of behaviors upon loss of MeCP2 in VIP interneurons. Adult mice lacking Mecp2 in all interneurons (DLX), VIP, PV or SST subclasses of neurons, compared to wild-type mice (CON). Mice were assessed in the elevated plus maze, marble burying and social interaction tests. Those lacking Mecp2 specifically in VIP interneurons showed impacts on marble burying and social interaction that were comparable to the effects of loss of Mecp2 in all interneurons. Image from Mossner J.M. et al. (2020).

The work was supported in part by a Pilot Award to SFARI Investigator Jessica Cardin. The authors generated a series of mouse lines lacking Mecp2 either globally, in all interneurons, or specifically in VIP, parvalbumin (PV) or somatostatin (SST) interneurons. As a measure of cortical network activity, they recorded high-frequency local field potential (LFP) activity, finding a decrease in LFP in mice lacking Mecp2 in VIP interneurons, which was similar to that seen in the pan-interneuron deletion. There was a particular decrease in cortical gamma-range activity, which is associated with cognition and sensory processing. Interestingly, hippocampal gamma-range activity was most affected by deletion of Mecp2 in SST interneurons, suggesting heterogeneity of its effects in different brain regions. In mice carrying the Mecp2 deletion in VIP interneurons, Cardin and colleagues also reported a loss of modulation of cortical-firing activity that is dependent on behavioral state, which mirrors that observed in the pan-interneuron deletion. Finally, they observed the same correlation when examining marble burying — a behavioral assay used to study phenotypes associated with repetitive behaviors.

Not all of the phenotypes examined were specific to VIP interneurons — for example, there were significant contributions to seizure frequency from loss of Mecp2 in each class of interneuron tested. But the overall impact of VIP interneurons on MeCP2-dependent biology was substantial, highlighting an emerging body of data that implicates these cells in the development of cortical circuits.


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