Abstract
Kv7.2 and Kv7.3 subunits, encoded by KCNQ2 and KCNQ3, form homo- or hetero-tetrameric voltage-gated potassium channels (Kv7 channel). Kv7 channels expressed in neurons produce a well characterized M-current that is a critical regulator of neuronal excitability by dampening repetitive firing. Gain-of-function (GoF) variants in KCNQ2 and KCNQ3 lead to severe early-onset neurodevelopmental disorders (KCNQ2- and KCNQ3-GoF-Encephalopathy). However, autism spectrum disorder (ASD) is a much more prominent feature in KCNQ3-GoF-Encephalopathy. This suggests for a Kv7.3 unique function during neurodevelopment. Interestingly, single nuclei RNA sequencing databases have revealed that KCNQ3 is the only KCNQ gene that is highly expressed in microglia in the human brain. Given the emerging evidence that microglia dysfunction is involved in the development of NDD and ASD, we hypothesize that KCNQ3-GoF variants affect microglia function which contributes to the already dysfunctional neuronal network.
In this project, I will build a human tripartite neuronal-microglia model (excitatory neurons, inhibitory neurons and microglia) derived from induced pluripotent stem cells that carry KCNQ-GoF variants, as well as control lines. With this model I will (i) investigate the function of Kv7.3 in microglia and (ii) unravel the contribution of each cell type to KCNQ3-GoF-Encephalopthy. Furthermore, this model will be used as a screening platform to perform a proof-of-concept study for RNA interference using antisense oligonucleotides as a targeted treatment strategy for KCNQ3-GoF-Encephalopathy. When successful, this approach could be extended to other types of neurodevelopmental disorders and drug screenings.
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