, 1999 and Custer et al , 2006) Thus, decays of the basal synapt

, 1999 and Custer et al., 2006). Thus, decays of the basal synaptic transmission in EPAC−/− neurons could be also due to a reduction of Sv2b expression. Our electrophysiological recordings show that LTP is impaired in EPAC−/− neurons, indicating that functions

of EPAC proteins extend beyond the basal synaptic transmission. LTP is an activity-dependent long-lasting enhancement of synaptic transmission and is one major form of plasticity in the central neurons (Nicoll and Malenka, 1995). The induction (during tetanus) of LTP requires activation of post-synaptic NMDA receptors (Nicoll and Malenka, 1995) whereas expression of LTP or a late phase of LTP (i.e., 60 min after the induction), is involved of a series of the genomic responses for rapid new gene expression (Soderling and Derkach, 2000 and Kelleher et al., 2004). Consistent with this 3-MA in vitro general idea, our data reveal that both NMDA

receptor channel activity at post-synaptic sites and LTP induction are normal in EPAC−/− neurons. Interestingly, our data demonstrate that a late phase of LTP is impaired in EPAC−/− mice and that this impairment correlates with a striking increase of miR-124 transcription, which caused Zif268 mRNA degradation. Zif268 is known as a critical transcriptional factor for stabilizing synaptic responses in LTP expression (Hall et al., 2000). Notably, either knockdown of miR-124 or expression of Zif268 is able to restore the capacity of EPAC−/− Adenylyl cyclase neurons to express LTP. Thus, EPAC signaling is directly linked with a key aspect of selleck compound the genomic responses including miR-124 transcription and Zif268 translation for LTP expression. Several rare nonsynonymous variants of EPAC genes were reported in patients with ASDs (Bacchelli et al., 2003) and one of them was found to be the loss of function mutation (Woolfrey et al., 2009). But the implications of these mutations in ASDs behaviors are not characterized yet. ASDs patients have been diagnosed as the abnormalities of social interactions and

mental retardation (Geschwind and Levitt, 2007, Kelleher and Bear, 2008 and Ramocki and Zoghbi, 2008). Additionally, the most human ASDs show poor language development and restricted and repetitive behaviors (Walsh et al., 2008 and Levy et al., 2009). In our present study, we show that genetic deletion of EPAC genes specifically defects the spatial learning and social interactions, suggesting a possibly mechanism by which the mutation of EPAC genes might reflect these ASDs behaviors. In conclusion, our results in the present studies provide genome-wide evidence that EPAC1 and EPAC2 proteins synergistically regulates miR-124 transcription and hence control Zif268 translation in the brain for processing spatial learning and social interactions.

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