A013 Study of OTX2 transcription factor in Huntington disease

<h3></h3> In early postnatal development of Huntington Disease (HD), cortical networks are transiently altered during a window of plasticity but self-normalize until the appearance of symptoms in adulthood (Barnat et al., Science, 2020; Braz et al., Science, 2022). The timing of other juvenile critical periods (CP) depends on the maturation of parvalbumin-expressing (PV) interneurons induced by the internalization of the non-cell autonomous transcription factor OTX2 coming from the choroid plexus. Changes in OTX2 levels can delay or activate plasticity in rodents (Spatazza et al., Cell Rep, 2013). These observations let us think that OTX2 levels could be modified in the choroid plexus or directly in PV cells to promote CP plasticity and prolong the compensatory mechanisms, with the aim to reverse HD mouse model phenotypes. To this end, we are firstly to investigate the interplay between OTX2 and HD impairments, by analyzing the distribution and maturation of PV cells in HD mice motor and visual cortices, as well as the morphology of choroid plexus and OTX2 expression in these structures. Secondly, we aim to treat in vitro HD mouse cortical and striatal cells with OTX2 in microfluidics in order to promote PV interneuron gating and restore cortico-striatal circuits. Finally, we will modify OTX2 levels in vivo to modulate CP timing, either with a secreted single-chain antibody against OTX2 or by local infusion of OTX2 protein, in order to consolidate compensatory mechanisms and rescue HD mouse model behavioral deficits.