Developmental alterations of indirect-pathway medium spiny neurons in mouse models of Huntington’s disease

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the gene encoding the Huntingtin protein (Htt). While symptoms, primarily characterized by progressive deterioration of the striatum and motor and cognitive functions, typically manifest in adulthood, recent studies have also highlighted developmental defects in HD. Indeed, alterations in cortical and striatal development have been observed in individuals carrying the mutation as early as in embryonic stages. However, despite the striatum being one of the most affected regions in HD, few studies have investigated potential developmental alterations in this structure, especially in the early weeks after birth. To address this question, we compared striatal development between wild-type (WT) mice and two murine models of HD, R6/1 and CAG140 mice crossed with reporter mice to identify D1- and D2-expressing medium spiny neurons (D1- and D2-MSNs). Using ex vivo electrophysiology and neuronal reconstruction, we observed that the maturation of electrical properties was selectively disrupted in D2-MSNs of the matrix compartment of HD mice during the first post-natal days. D2-MSNs arbor also an increased dendritic complexity. When studying the establishment of striatal afferents, we observed that cortico-striatal glutamatergic transmission was specifically reduced in D2-MSNs during the second postnatal week. All these alterations were transient before the circuit normalized on its own after the second postnatal week. These anatomical and electrophysiological data highlight the significant impact of the Htt mutation on numerous striatal development processes during the postnatal period. Interestingly, we observed that these alterations specifically affect MSNs in the indirect pathway. This preferential vulnerability aligns with the early death of these neurons in adulthood, suggesting that early treatment of these alterations could potentially modify the disease’s progression.