GW3965 modulates CA1 fEPSPs and prevents synaptic plasticity impairment mediated by Aβ42-oligomers.

(A) Representative examples of evoked fEPSPs changes upon 0,5 μM GW3965 application (Blue dots in B), red arrow before, blue arrow identify fEPSP after 75 min of drug application. (B) Shown are the time-courses of field CA1 fEPSPs evoked every 30 sec (y axis = changes in fEPSP slope over time) after the following treatments: 1) GW3965 (0.1 μM) [GW 0.1 μM—yellow dots]. 2) GW3965 (0.5 μM) [GW 0.5 μM, blue dots] 3) Slices incubated for 60 min with 25 μM anisomycin (ANI) and treated with GW3965 (0.5 μM) [GW+ANI—red dots] 4) Slices incubated for 60 min with 300 μM Cicloheximide (CHX) and treated with 0.5 μM GW3965 [GW+CHX—green dots] and 5) Vehicle treated slices [control—black dots]; n = 4 per group, 3–6 months of age. In all cases a 15 min baseline fEPSP was obtained before pharmacological manipulations and fEPSP slopes were normalized to the first response. (C) Representative traces from B at baseline and 75 min after each treatment, as indicated. (D) Long term potentiation (LTP) was elicited by one train of 100 stimuli at 100 Hz (arrow), fEPSPs were evoked every 30 sec. Shown are normalized fEPSP slope values, the data is presented as mean +/-SEM. Slices were incubated with oligomeric (oAβ42), scrambled (sAβ) or vehicle (control) during 40 min before recording and LTP was induced after 15 min of baseline. [Control-vehicle treated, n = 7- black dots; oAβ42 100nM, n = 4—gray dots; oAβ42 200 nM, n = 5—red dots and sAβ 200 nM, n = 6—purple dots]. (E) Shown are time-courses of fEPSPs responses after high frequency stimulation (HFS) as in D, in slices incubated with GW3965 0.1 μM for 60 min and 200 nM oAβ42 for 40 min [GW+ oAβ42, n = 5—blue dots]. For comparative purposes traces of slices incubated with 200 nM oAβ42 [red dots] and controls [black dots] from D were plotted. (F) Shown are traces of fEPSP responses in slices incubated with GW3965 0.1 μM for 60 min and 200 nM oAβ42 for 40 min. After 30 min of HFS, 25 μM anisomycin (ANI) was added to the bath [GW+ oAβ42+ANI], as indicated by line. (G) Bar graphs and two way ANOVAs analysis of fEPSPs changes from baseline at the 50–60 min interval after HFS in control, oAβ42 200 nM, [GW 0.1 μM + 200 nM oAβ42] and [GW + oAβ42 200nM + ANI 25 μM], ** denotes p<0.01.