Recent research suggests that cross-talk between the Ca2+, cAMP, and Erk/MAP kinase regulatory systems is critical for specific types of synaptic plasticity as well as long-term memory (LTM). There is also increasing evidence that Ca2+ stimulation of the CREB/CRE (cAMP response element)-transcriptional pathway plays a pivotal role in long-lasting, long-term potentiation (L-LTP) and LTM. For example, we recently discovered that stimulus paradigms that generate L-LTP or training for contextual and passive avoidance learning stimulate CRE-mediated transcription and CREB phosphorylation in the hippocampus of mice. Ca2+ activation of CRE-mediated transcription in neurons and the generation of L-LTP in hippocampal slices both depend upon the coactivation of Erk/MAP kinase and cAMP-dependent protein kinase (PKA). This proposal focuses on the role of the Ca2+-stimulated adenylyl cyclases, AC1 and AC8, in synaptic plasticity and hippocampus-dependent learning. We hypothesize that Ca2+ activation of AC1 or AC8, generates the critical cAMP signal necessary for Ca2+-stimulation of CRE-mediated transcription, L-LTP, and some forms of LTM. We also hypothesize that AC1 or AC8 may be crucial for other forms of synaptic plasticity including mossy fiber/CA3 LTP. We propose to determine if Ca2+ stimulates CREB phosphorylation and activates CRE-mediated transcription in cultured hippocampal neurons from AC1, AC8, or AC1 x AC8 (DKO) mutant mice. We will determine if the stimulus paradigm that generates L-LTP or training for hippocampus-dependent learning activates CRE-mediated transcription in hippocampal slices from DKO mutant mice or PKA mutant mice. We propose to determine if defects in hippocampus-dependent learning in DKO mutant mice can be overridden by drugs that elevate cAMP or activate PKA. We will also characterize mossy fiber/CA3 LTP in DKO mutant mice. This project should provide fundamental insight concerning molecular mechanisms for neuroplasticity and may ultimately contribute to the development of drugs to treat patients who have deficiencies in learning or memory.
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