CA2+ STIMULATED ADENYLYL CYCLASES AND NEUROPLASTICITY

描述：（申请人摘要） 最近的研究表明，Ca 2+，cAMP和Erk/MAP之间的串扰 激酶调节系统对于特定类型的突触可塑性至关重要 以及长期记忆（LTM）。越来越多的证据表明，Ca 2 + CREB/CRE（cAMP反应元件）-转录途径的刺激 在长时程增强（L-LTP）和LTM中起关键作用。 例如，我们最近发现，产生L-LTP的刺激模式 或情境和被动回避学习刺激的培训 小鼠海马中CREB介导的转录和磷酸化。 Ca 2+激活神经元中CREE介导的转录和 海马脑片的L-LTP均依赖于Erk/MAP激酶的共激活 和cAMP依赖性蛋白激酶（PKA）。本建议侧重于以下方面的作用： Ca 2+刺激的腺苷酸环化酶AC 1和AC 8在突触可塑性中的作用， 校园依赖学习。我们假设，钙激活AC 1或 AC 8产生Ca 2+刺激细胞所必需的关键cAMP信号， CRE介导的转录，L-LTP和某些形式的LTM。我们还假设 AC 1或AC 8可能对其他形式的突触可塑性至关重要， 苔藓纤维/CA 3 LTP。我们建议确定Ca 2+是否刺激CREB 磷酸化并激活CRE介导的转录， 来自AC 1、AC 8或AC 1 × AC 8（DKO）突变小鼠的海马神经元。我们将 确定产生L-LTP的刺激范式或训练是否 依赖于海马区的学习激活CREE介导的转录， 来自DKO突变小鼠或PKA突变小鼠的海马切片。我们建议 确定DKO突变小鼠的海马区依赖性学习缺陷是否可以 会被升高cAMP或激活PKA的药物所抵消。我们还将 表征DKO突变小鼠中苔藓纤维/CA 3 LTP。这个项目应该 提供有关神经可塑性的分子机制的基本见解 并可能最终有助于药物的开发，以治疗 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.