Figure 1.

Intracerebroventricular AAV9.Cln3 gene therapy given at p0 normalizes neuronal network dynamics in vivo at age 12 months

(A) p0 ICV injection of AAV9.Cln3 restored Cln3 expression in Cln3^{Δex78/Δex78} mouse brain at age 12 months, with levels in the Cln3^{Δex78/Δex78} hemisphere contralateral to the injection site reaching 24.5% ± 4.7% of heterozygous controls. (B) Subunit C of the mitochondrial ATP synthase (SCMAS) accumulation is partially prevented in the hippocampus ipsilateral to the injection site of Cln3^{Δex78/Δex78} mice treated with AAV9.Cln3 (n = 3–4 mice, one-way ANOVA, followed by Tukey’s multiple comparisons test). Gene replacement corrects circuit function measured on intracranial EEG, including (C) epileptiform spiking rates throughout the cortex and (D) background frequency band composition in the motor cortex. Groups: Cln3^WT/WT (blue); Cln3^WT/Δex78 (black); Cln3^{Δex78/Δex78} (red); Cln3^{Δex78/Δex78} + AAV9.CLN3 (gray). N = 5–6 animals/condition. Results from 12 h of recordings were averaged for each animal shown as an individual circle. Spikes were analyzed by two-way ANOVA, followed by Tukey’s multiple comparisons test to compare between genotype groups. Frequency bands were analyzed by two-way ANOVA by band and genotype, followed by Tukey’s multiple comparisons test (significant results of multiple comparison testing shown as ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001). Data are shown as mean ± SEM.