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bioRxiv · 10.1101/2024.05.30.596683

Loss of the MeCP2 gene in parvalbumin interneurons leads to an inhibitory deficit in the amygdala and affects its functional connectivity.

Liiwand, M.·Haikonen, J.·Kokinovic, B.·Molchanova, S. M.·Aitta-aho, T.·Lauri, S. E.·Ryazantseva, M.
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Abstract

BackgroundMECP2 gene is located in the X-chromosome and encodes a methyl-CpG-binding protein involved in transcription regulation. The loss-of-function mutation of the MECP2 gene, leads to severe neurodevelopmental syndrome, Rett syndrome. Clinical picture of Rett syndrome includes, among other symptoms, social deficits and heightened anxiety. The amygdala is involved in the regulation of social behavior as well as fear and anxiety. Here, we investigated the effect of the MeCP2 gene ablation in the parvalbumin interneurons on the microcircuit and functional connectivity of the amygdala. MethodsMales with conditional knock-out of the MeCP2 gene in the parvalbumin interneurons were used as a genetic mouse model of MeCP2 loss in parvalbumin interneurons. Littermates with the intact gene were used as controls. Ex-vivo brain slice electrophysiology, combined with pharmacology and optogenetics, was used to characterize microcircuits within the lateral amygdala. Synaptic currents and excitability of parvalbumin interneurons and principal neurons were analyzed by a whole-cell patch clamp. In-vivo functional ultrasound was used to visualize the connectivity within the amygdala-ventral hippocampus-prefrontal cortex triad. ResultsLoss of MeCP2 in parvalbumin interneurons significantly reduced the GABAergic synaptic input to the principal neurons in the lateral amygdala. The decreased inhibitory drive was accompanied by an increase in the excitability of principal neurons in the lateral amygdala. The in vivo functional connectivity of the amygdala-ventral hippocampus and amygdala-prefrontal cortex was significantly reduced in conditional knock-outs compared to their littermates with the intact gene in the X chromosome. ConclusionsOur study characterized the consequences of MeCP2 gene loss in the parvalbumin interneurons on the amygdala connectivity and microcircuit and provided evidence supporting the previous findings on the role of interneurons in the functional deficit observed in animal models with MeCP2 loss.

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Liiwand, M., Haikonen, J., Kokinovic, B., Molchanova, S. M., Aitta-aho, T., Lauri, S. E., Ryazantseva, M.. 2024-05-30. Loss of the MeCP2 gene in parvalbumin interneurons leads to an inhibitory deficit in the amygdala and affects its functional connectivity.. https://doi.org/10.1101/2024.05.30.596683

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