Figure 5. CBX, a drug that reduces storage burden, cannot correct hypoexcitability of the DG and worsens hypoexcitability of the hilus and CA3 in early-stage CLN3 disease.

(A–C) Hippocampal slices from 2-month-old CLN3^–/– mice treated with 2 weeks of 20 mg CBX, a dose that reduces storage burden and normalizes endocytosis in vivo, show residual hypoexcitability of the DG after PP stimulation, as measured by VSDI response as compared with untreated CLN3^–/– slices. (D–F) CBX treatment worsened hypoexcitability of the hilus and CA3 after SC stimulation as compared with untreated CLN3^–/–. Group sizes (n = slices, N = mice): 2-month PP stimulation untreated n = 26, N = 5; CBX-treated n = 25, N = 5; 2-month SC stimulation untreated n = 11, N = 5; CBX-treated n = 20, N = 5. Areas of statistical significance identified using a permutation sampling method; for regions of significance with P < 0.05, the difference in fluorescence change (ΔF/F_Untreated – ΔF/F_CBX) is shown. Panel A reproduced from Figure 1B. Panel D reproduced from Figure 3B.