Restoring cortical disinhibition improves Huntington’s disease phenotypes

Animals All animal procedures were performed in accordance with guidelines set forth and protocols approved by the UCSD Institutional Animal Care and Use Committee and the US National Institutes of Health, as well as by the Government of Upper Bavaria, Germany (animal protocols 55.2-1-54-2532-168-2014, 55.2-1-54-2532-19-2015, 55.2-2532.Vet_02-20-05 and 55.2-2532.Vet_02-19-83). R6/2 mice 16 transgenic for the 5′ end of the human huntingtin gene were obtained from Jackson Laboratories (stock no. 002810) and maintained by crossing R6/2 males to F1 C57BL/6–CBA females. Knock-in zQ175DN 19 , 20 mice were obtained from Jackson Laboratories (stock no. 029928) and maintained on a C57BL/6 background. The presence of the transgene or knock-in was verified by PCR with the following primers: R6/2: forward, 5′CCGCTCAGGTTCTGCTTTTA-3′, reverse, 5′-TGGAAGGACTTGAGGGACTC-3′. zQ175DN: forward, 5′- GCGGGCTTATACCCCTACAG-3′, reverse, 5′-TCCAGGACAGCCAGAGCTAC-3′. CAG repeat length was determined by Laragen for all experimental groups. Spontaneous behavioural experiments on the wheel were performed at the Max Planck Institute for Biological Intelligence, and motorized ladder experiments were performed at the UCSD. Separate batches of R6/2 mice were used for these two sets of experiments, and the CAG repeat lengths were different between these two groups (202 ± 13 and 157 ± 6 for the Max Planck Institute and UCSD, respectively, mean ± s.d.), which led to different speeds of disease progression. …