Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP

It is hypothesized that Ca2+ stimulation of calmodulin (CaM)-activated aden ylyl cyclases (AC1 or AC8) generates cAMP signals critical for late phase L TP (L-LTP) and long-term memory (LTM). However, mice lacking either AC1 or AC8 exhibit normal L-LTP and LTM. Here, we report that mice lacking both en zymes (DKO) do not exhibit L-LTP or LTM. To determine if these defects are due to a loss of cAMP increases in the hippocampus, DKO mice were unilatera lly cannulated to deliver forskolin. Administration of forskolin to area CA 1 before training restored normal LTM. We conclude that Ca2+-stimulated ade nylyl cyclase activity is essential for L-LTP and LTM and that AC1 or AC8 c an produce the necessary cAMP signal.