Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice

PAK inhibition partially rescues increased density and length of dendritic spines in FMR1 KO mice. (A) Representative dendritic segments of layer II/III pyramidal neurons from WT (n = 20 neurons; two mice), dnPAK TG mice (n = 30 neurons; three mice), FMR1 KO mice (n = 20 neurons; two mice), and double mutant dnPAK TG;FMR1 KO mice (dMT; n = 40 neurons; four mice). (B) On each primary apical dendritic branch, 10 consecutive 10 μm-long dendritic segments were analyzed to quantify spine density. Spine density in dMTs was comparable to WT controls in all dendritic segments except segments 7 and 8 (P > 0.05 in segments 1–6, 9, and 10; P < 0.01 in segments 7 and 8). (C) Mean spine density in dMTs (1.28 ± 0.02) was significantly lower than that in FMR1 KO mice (1.60 ± 0.02; P < 0.001) and significantly higher than that in dnPAK TG mice (1.06 ± 0.01; P < 0.001). ANOVA, P < 0.0001. ∗∗∗, P < 0.001. (D) As for spine length, FMR1 KO neurons (444 spines) exhibited a significant shift in the overall spine distribution toward spines of longer length compared with WT neurons (406 spines; Kolmogorov-Smirnov test: P < 0.05), whereas dnPAK TG neurons (630 spines) exhibited the opposite shift to shorter spines (P < 0.01). In contrast, spine length distribution in dMT neurons (785 spines) overlapped well with WT neurons and is significantly different from FMR1 KO neurons (P < 0.01).