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. Author manuscript; available in PMC: 2013 Jun 21.
Published in final edited form as: Neuron. 2012 Jun 21;74(6):1031–1044. doi: 10.1016/j.neuron.2012.05.009

Figure 4. Sustained phenotypic reversal from transient ASO infusion into the CNS of BACHD mice for 8 months after treatment termination.

Figure 4

(A) Schematic of treatment paradigms (B-D). At 6 months of age, BACHD mice were infused for two weeks with 50μg/day of an ASO that targets human huntingtin (HuASO), ASOs that have no target in the mouse genome (CntASO) or vehicle (Saline). Non-transgenic littermates were infused with vehicle (Saline).

(B) Levels of human huntingtin mRNAs 2 months post-treatment, as measured by qPCR in BACHD mice treated at 6 months of age (n=5 per treatment, data are expressed as mean % ± SEM, two-tailed unpaired t-test, p<0.0001).

(C) Motor performance on a rotarod between ages 6 and 12 months, and measured every 4 weeks. Asterisks denote statistically significant changes compared to BACHD HuASO treated animals (n=8–13).

(D) Open-field performance 2 (8 months old, p=0.111), 4 (10 months old, p=0.027) and 6 (12 months old, p=0.034) months post-treatment in BACHD mice (non-transgenic, n=3–6; BACHD, n=12–16).

(E) Schematic of treatment paradigm (F–K). At 6 months of age, BACHD mice were infused for two weeks with 50μg/day of HuASO (red) or saline (black). Non-transgenic mice are included as behavioral controls (white).

(F) Performance of mice 6 and 9 months after ASO infusion determined by time mobile in an open-field test, p=0.002 and p=0.016, respectively (n=6–8).

(G) Rotarod performance after two consecutive days of training at 9 months post-treatment (15 months of age), p<0.0001 (n=6–8).

(H) Light/dark choice at 15 months of age, p=0.016 (n=6–8). In all instances (F–H), saline treated BACHD mice performed significantly worse than non-transgenic and HuASO treated BACHD mice (One-way ANOVAs and Tukey’s post hoc tests).

(I) Immunoblot of huntingtin protein 2 and 9 months post-treatment, GAPDH is used as a loading control.

(J) 9 months post-treatment qPCR was used to quantify mouse and human huntingin mRNA levels. qPCR are expressed as mean ± SEM percent (%) of huntingtin mRNA relative to saline treated controls (n=6 per treatment).

(K) Immunohistochemical (IHC) staining for mutant huntingtin aggregates with anti-polyglutamine antibody (3B5H10) (brown) and nuclear counterstain hematoxylin (blue), 9 months post-treatment. Scale bar: 50μm. Representative images, n=6 BACHD per treatment. See also Figure S4.