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. 2020 Nov 2;117(46):29069–29079. doi: 10.1073/pnas.2008306117

Fig. 7.

Fig. 7.

Stretch-induced tau mislocalization and hyperphosphorylation mediate synaptic dysfunction. (A–L) Effect of GSK3β and CDK5 inhibition on mEPSC dynamics. A, D, G, and J are representative mEPSC recordings from neurons exposed to stretch. B, E, H, and K show cumulative frequency of mEPSC amplitudes (black, unstretched control; red, stretched and treated; bins, 1 pA). C, F, I, and L show cumulated frequency of mEPSC peak-to-peak period (black, untreated control; teal, stretched and treated; bins, 50 ms). (A–C) Untreated. (D–F) Pretreated with 500 nM CHIR990021 to inhibit GSK3β. (G–I) Pretreated with 500 nM Roscovitine to inhibit CDK5. (J–L) Pretreated with both CHIR99021 and Roscovitine. (M) Quantification of mEPSC amplitudes (black line, median; red line, mean; box, 25 to 75%; whisker, 10 to 90%). (N) mEPSC frequency (black line, median; teal, mean; box, 25 to 75%; whisker, 10 to 90%). (O) Proposed molecular framework of the postsynaptic deficits and presynaptic suppression caused by mechanical injury. While most postsynaptic deficits depend upon tau, other factors independent upon tau may contribute to presynaptic deficits. For cumulative frequency distribution plots, K-S tests were used to compare treated and/or stretched groups to unstretched–untreated controls. D/Dcrit: B, 4.31; C, 5.48; E, 4.79; F, 3.33; H, 5.11; I, 4.30; K, 1.82; L, 2.98; α = 0.05 for all. Cells/mEPSCs: control, 18/4,360; DMSO, 13/1,464; unstretched–both drugs, 11/1,571; stretched–untreated, 23/3139; CHIR99021, 10/2,481; Roscovitine, 11/1,352; stretched–both drugs, 14/1,255. In all plots, *P < 0.05, ***P < 0.001 compared to control, and NS is not significant. Note that K-S test significance in K is due to variations in low-amplitude events, not a difference in the means (M). Were these small events (<7pA) excluded, the treated and control groups would not be significantly different. The two curves in K are obviously much closer than those in B, E, and H; nevertheless, it is possible that the highly sensitive nonparametrical K-S test can still detect some residual effects of TBI.