I011 Functional impacts of Huntingtin lowering on the synaptic activity of neuron-glia networks derived from human induced pluripotent stem cells

<h3></h3> Several clinical trials that have been conducted and are currently underway explore Huntingtin (HTT) lowering approaches^{1 2} which target non-selectively both the wild type HTT (wt-HTT) and the mutant Huntingtin (mut-HTT) isoforms^3–5 responsible for Huntington’s disease (HD).⁶ The rationale behind these trials is based on the autosomal dominant inheritance of HD, supporting the idea that mut-HTT exerts its harmful effects through a toxic gain-of-function and/or a dominant-negative mechanism.^7–9 Despite growing descriptions of HTT involvement both during development^10–12 and in adult brain functions,¹³ the precise amount of HTT needed for healthy neurons remains unclear. Here, we address this question by examining how HTT loss affects human neuronal network formation, synaptic maturation, and homeostasis in vitro. Our findings establish that a loss of more than two-thirds of the wt-HTT protein in healthy human cortical neuronal networks impairs the maturation of dendritic arborization and the acquisition of network-wide synchronized activity. Importantly, these defects were also observed when lowering both wt-HTT and mut-HTT in neuronal networks derived from HD patient’s cells. Our study underscores the critical need to precisely understand HTT’s role in neuronal health. It also emphasizes the potential risks of excessive HTT loss associated with non-selective therapeutic approaches targeting both wt and mutant HTT isoforms in HD patients. <h3>References</h3> Yamamoto, <i>et al</i>. 2020, DOI: 10.1016/S0092-8674(00)80623-6 Kaemmerer, <i>et al</i>. 2019. DOI : 10.2147/DNND.S163808 Caron, <i>et al</i>. 2020. DOI: 10.1093/nar/gkz976 McColgan, <i>et al</i>. 2023. DOI : 10.1056/NEJMc2300400 Thomson, <i>et al</i>. 2023. DOI: 10.1093/brain/awac458 Group, <i>et al</i>. 1993. DOI: 10.1016/0092-8674(93)90585-e Bates, <i>et al</i>. 2015. DOI : 10.1038/nrdp.2015.5 Guo, <i>et al</i>. 2018. DOI : 10.1038/nature25502 Rubinsztein, <i>et al</i>. 2003. DOI : 10.1017/S1462399403006549 Barnat, <i>et al</i>. 2017. DOI : 10.1016/j.neuron.2016.11.035 Dragatsis, <i>et al</i>. 2000. DOI: 10.1038/81593 Reiner, <i>et al</i>. 2001. DOI: 10.1523/JNEUROSCI.21-19-07608.2001 Saudou et Humbert 2016. DOI: 10.1016/j.neuron.2016.02.003