CA2+ STIMULATED ADENYLYL CYCLASES AND NEUROPLASTICITY

描述：(申请人摘要) 最近的研究表明，钙离子、cAMP和ERK/MAP之间的相互作用 激酶调节系统对特定类型的突触可塑性至关重要 以及长时记忆(LTM)。还有越来越多的证据表明，钙离子 刺激CREB/Cre(cAMP反应元件)转录途径 在长时间、长时程增强(L-长时程增强)和长时程增强中起着关键作用。 例如，我们最近发现，产生L-LTP的刺激范式 或对情境和被动回避学习的培训刺激 Cre介导的小鼠海马区转录和CREB磷酸化。 Cre介导的神经元转录的Ca2激活及其产物的产生 海马脑片L-LTP均依赖ERK/MAPK的共激活 和cAMP依赖的蛋白激酶(PKA)。这项建议侧重于 钙离子刺激的腺酰环化酶AC1和AC8在突触可塑性和 依赖海马体的学习。我们假设AC1或AC1的钙激活 AC8产生钙离子刺激所需的关键cAMP信号 Cre介导的转录，L-LTP，以及一些形式的LTM。我们还假设 AC1或AC8可能对其他形式的突触可塑性至关重要，包括 苔藓纤维/CA3 LTP。我们建议确定钙是否刺激CREB 磷酸化并激活Cre介导的转录 AC1、AC8或AC1×AC8(DKO)突变小鼠的海马神经元。我们会 确定产生L-LTP或训练的刺激范式 海马区依赖学习激活Cre介导的转录 DKO突变小鼠或PKA突变小鼠的海马片。我们建议 确定DKO突变小鼠的海马区依赖学习缺陷是否可以 被升高cAMP或激活PKA的药物覆盖。我们还将 DKO突变小鼠苔藓纤维/CA3LTP的特征。这个项目应该 提供关于神经可塑性的分子机制的基本见解 并最终可能有助于药物的开发，以治疗那些 在学习或记忆方面有缺陷。

DESCRIPTION: (Applicant's Abstract) 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.