Loss of the Mecp2 gene in parvalbumin interneurons leads to an inhibitory deficit in the amygdala and affects its functional connectivity.

backgroundThe MECP2 gene is located on the X chromosome and encodes a methyl-CpG-binding protein 2 involved in transcriptional regulation. Loss-of-function mutations in the MECP2 gene lead to Rett syndrome, a severe neurodevelopmental disorder. The clinical picture of Rett syndrome includes, among other symptoms, social deficits, learning impairment, and heightened anxiety. The amygdala is a brain region responsible for emotional learning and is involved in the regulation of social behaviour as well as fear and anxiety. Parvalbumin interneurons tightly control the excitability, oscillation and synchronisation of the amygdala network, which are relevant to its functions. Here, we investigated the effects of Mecp2 gene ablation in parvalbumin interneurons on the microcircuit and functional connectivity of the mouse amygdala.

methodsMale mice with conditional knockout of the Mecp2 gene in parvalbumin interneurons were used as a genetic mouse model. Littermates with an intact gene were used as controls. Ex vivo brain slice electrophysiology, combined with pharmacology and optogenetics, was utilised to characterise microcircuits within the lateral amygdala. In vivo functional ultrasound imaging was used to visualise the connectivity within the amygdala-ventral hippocampus-prefrontal cortex network triad.

resultsLoss of Mecp2 in parvalbumin interneurons significantly attenuated GABAergic synaptic input to principal neurons in the lateral amygdala. The deficit in inhibition was accompanied by higher excitability of local principal neurons in adult animals. A deficient in vivo functional connectivity of the amygdala with the ventral hippocampus and prefrontal cortex was observed in conditional knockouts. LIMITATIONS: This study used only male mice. Mecp2 knockout males exhibit shorter latency to symptom onset and lower phenotypic variability, making them suitable for mechanistic studies. Since previous studies in the field used males, we aimed to advance the existing body of research using the same approach. Finally, the link between the effects observed and possible behavioural alterations needs further investigation.

conclusionsOur study characterised the consequences of Mecp2 loss in parvalbumin interneurons on amygdala microcircuit function and connectivity within the prefrontal cortex‒amygdala‒hippocampus triad. It also provided evidence that supports and complements previous findings on the role of interneurons in the functional deficits observed in Mecp2 knockout animal models.