Corticostriatal maldevelopment in the R6/2 mouse model of juvenile Huntington's disease

• Published in: Neurobiology of disease 2025-01, Vol.204, p.106752, Article 106752
• Main Authors: Cepeda, Carlos, Holley, Sandra M., Barry, Joshua, Oikonomou, Katerina D., Yazon, Vannah-Wila, Peng, Allison, Argueta, Deneen, Levine, Michael S.
• Format: Article
• Language: English
• Subjects: Animals; Cerebral Cortex - growth & development; Cerebral Cortex - pathology; Cerebral Cortex - physiopathology; Corpus Striatum - pathology; Development; Disease Models, Animal; Ex vivo electrophysiology; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - genetics; Huntington Disease - pathology; Huntington Disease - physiopathology; Juvenile Huntington's disease; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pyramidal Cells - pathology; R6/2 mouse; Synaptic activity
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2024.106752

There is a growing consensus that brain development in Huntington's disease (HD) is abnormal, leading to the idea that HD is not only a neurodegenerative but also a neurodevelopmental disorder. Indeed, structural and functional abnormalities have been observed during brain development in both humans and animal models of HD. However, a concurrent study of cortical and striatal development in a genetic model of HD is still lacking. Here we report significant alterations of corticostriatal development in the R6/2 mouse model of juvenile HD. We examined wildtype (WT) and R6/2 mice at postnatal (P) days 7, 14, and 21. Morphological examination demonstrated early structural and cellular alterations reminiscent of malformations of cortical development, and ex vivo electrophysiological recordings of cortical pyramidal neurons (CPNs) demonstrated significant age- and genotype-dependent changes of intrinsic membrane and synaptic properties. In general, R6/2 CPNs had reduced cell membrane capacitance and increased input resistance (P7 and P14), along with reduced frequency of spontaneous excitatory and inhibitory synaptic events during early development (P7), suggesting delayed cortical maturation. This was confirmed by increased occurrence of GABAA receptor-mediated giant depolarizing potentials at P7. At P14, the rheobase of CPNs was significantly reduced, along with increased excitability. Altered membrane and synaptic properties of R6/2 CPNs recovered progressively, and by P21 they were similar to WT CPNs. In striatal medium-sized spiny neurons (MSNs), a different picture emerged. Intrinsic membrane properties were relatively normal throughout development, except for a transient increase in membrane capacitance at P14. The first alterations in MSNs synaptic activity were observed at P14 and consisted of significant deficits in GABAergic inputs, however, these also were normalized by P21. In contrast, excitatory inputs began to decrease at this age. We conclude that the developing HD brain is capable of compensating for early developmental abnormalities and that cortical alterations precede and are a main contributor of striatal changes. Addressing cortical maldevelopment could help prevent or delay disease manifestations. [Display omitted] •The development of cortical and striatal projection neurons in R6/2 Huntington's disease mice is abnormal.•Abnormalities of cortical projection neurons occur earlier and are more severe than those of striatal projection neuron