To extend analysis of synaptic functions, we examined whether LTP, an activity-dependent

long-lasting enhancement of synaptic transmission (Nicoll and Malenka, 1995), was altered in EPAC null alleles. In this study, we performed the intracellular sharp electrode recordings of the excitatory postsynaptic potentials (EPSPs) in CA1 pyramidal neurons. We observed that brief high-frequency stimulation (tetanus) increased the peak amplitudes of the evoked EPSPs in control littermates. This increase (LTP) was maintained over 90 min (Figures 2G and 2H, 1.78 ± 0.15, n = 12 recordings/6 mice/group). In EPAC−/− neurons, however, a short-term enhancement but not LTP was found; the peak amplitudes decayed to the basal levels after 30 min of the tetanus (1.05 ± 0.71, n = 14 recordings/7 mice/group, p < 0.01). Similar to KU-57788 cell line CA1 pyramidal neurons, an absence of LTP was observed in the EPAC−/− granule cells (Figure 2H). LTP deficits in EPAC−/− cells was not due to the developmental abnormalities because it was found in the inducible EPAC−/− mice (IN-EPAC−/−), in which EPAC1 gene was deleted

after development was completed (1.09 ± 0.79 in CA1 and 1.11 ± 0.68 in the dentate granule cells, respectively; Figures 2G and 2H). It should be mentioned that BTK inhibitor in vivo there was a reduction of synaptic strength in EPAC−/− neurons in response to the elevated stimulus intensities under the basal condition (Figure 2A). Thus, the failure expression of LTP in EPAC−/− mice could be a functional consequence of

a general synaptic deficit. To investigate this possibility, we examined Terminal deoxynucleotidyl transferase the capacity of EPAC−/− neurons for LTD expression by applying 300 stimuli over the course of 3 min. We found that the magnitude of LTD did not differ among groups (Figure 2I). Thus, EPAC null mutation specifically impairs LTP. LTP of synaptic transmission in the hippocampus is widely considered as a cellular substrate of spatial learning and memory formation (Nicoll and Malenka, 1995 and Kessels and Malinow, 2009). Thus, we asked whether the deficits of LTP, particularly in its late phase, were paralleled with the abnormalities in spatial information acquisition. To answer this question, we carried out the Morris water maze tests. Prior to the tests, we tested the exploratory activity and locomotion of mice in the open field. We measured the floor plane movements (Figure 3A) and vertical plane entries (i.e., rearing, Figure 3B) as well as the stereotypic behaviors (i.e., grooming, Figure 3C) and found that all parameters examined were normal in EPAC null alleles (n = 16 mice per group). We next trained adult male mice in the hidden platform version of the Morris water maze with four trials per day. Consistent with previous studies using pharmacological reagents (Ouyang et al., 2008), we found that EPAC null mutant mice had a significant longer latency and swim path length to reach the platform, compared to the other groups (Figure 3D, n = 16 mice/group, p < 0.01).