B007 Selective developmental alterations of striatal indirect-pathway neurons in mouse models of Huntington’s disease

<h3>Background</h3> Huntington’s disease (HD) is typically defined as a late-onset disease, however, recent evidence has revealed its impact on human neurodevelopment. Furthermore, early alterations of cortical development have also been observed in animal models of HD. Despite the striatum being severely affected in adult HD carriers, its potential developmental alterations, particularly in the early days after birth, remain underexplored. This postnatal period is crucial for shaping the striatal network and its connections with the rest of the brain, so any disruption of these finely coordinated mechanisms could significantly impact the circuit’s later function. <h3>Aims</h3> We longitudinally compared striatal development between wild-type mice and two murine models of HD, R6/1 and CAG140 mice. <h3>Methods</h3> Employing immunohistochemistry, ex vivo electrophysiology and image reconstructions techniques, we observed the establishment of striatal neurons morphological and electrophysiological properties. <h3>Results</h3> During the first postnatal days, we observed that the maturation of electrical and morphological properties was specifically disrupted in indirect-pathway neurons (D2-MSNs) of HD mice, with a decrease in their excitability (Figure 1) and an increased dendritic complexity (Figure 2). We also observed that cortico-striatal transmission was specifically reduced in D2-MSNs during the second postnatal week (Figure 3). All these alterations were transient, occurring during the early postnatal days, before the circuit normalized on its own after the second postnatal week. <h3>Conclusion</h3> We observed that striatal alterations selectively affect indirect-pathway MSNs. This preferential vulnerability aligns with the early death of these neurons in adulthood, suggesting that treatment of these alterations could potentially modify the disease’s progression.