Figure 7.

Pharmacological Manipulation of Epac Activity Impairs LTP In Vitro and Motor Learning In Vivo without Affecting Synaptic Transmission

(A) Epac antagonist ESI-05 prevents PF-PC LTP induced by tetanic PF stimuli.

(B) Epac activation through incubation with 8pCPT potentiates AMPAR currents (open triangles). As a consequence, a minimal 30 min incubation with 8cCPT fully occludes LTP induction (black squares) compared with LTP induction in the absence of 8cCPT (gray circles).

(C) Eye-movement phase values in WT mice that are injected with 10 mg/kg ESI-05 (open blue circles) or with vehicle only (black circles) are virtually identical during visuovestibular mismatch training when the light is on.

(D) During the catch trials in the dark, the phase shift of VOR adaptation in the mice injected with 10 mg/kg ESI-05 is significantly delayed compared with the phase shift in their littermates injected with vehicle only.

(E) Polar plot of the combined gain and phase data shows a common learning trajectory and comparable initial gain, yet a different final outcome, for both groups. In the inset, the final VOR reached after 5 days of training is amplified to visualize the magnitude of the gain difference (red arrow) between ESI-05-injected and vehicle-injected mice.

(F) Four representative eye-velocity traces of the VOR before (left) and after (right) phase-reversal training show that, whereas both ESI-05 and vehicle-injected mice show equal baseline performance and both are able to flip the phase of the VOR, the magnitude of the VOR reached after the training is substantially different.

(G) Both learning extent and consolidation during the phase-reversal task are significantly smaller in the mice injected with ESI-05 than in those injected with vehicle only (T2 test p < 0.05).

(H) Impaired motor learning after ESI-05 injections does not correlate with decreased transmission at PF-PC synapses. The PC mEPSC amplitude and frequency did not change upon injection of WT mice with ESI-05 or upon incubation of WT slices with ESI-05.

Error bars indicate SEM; ^∗ indicates p < 0.05.