Hippocampal long-term depression and depotentiation are defective in mice carrying a targeted disruption of the gene encoding the RI beta subunit of cAMP-dependent protein kinase.

The cAMP-dependent protein kinase (PKA) has been shown to play an important role in long-term potentiation (LTP) in the hippocampus, but little is known about the function of PKA in long-term depression (LTD). We have combined pharmacologic and genetic approaches to demonstrate that PKA activity is required for both homosynaptic LTD and depotentiation and that a specific neuronal isoform of type I regulatory subunit (RI beta) is essential. Mice carrying a null mutation in the gene encoding RI beta were established by use of gene targeting in embryonic stem cells. Hippocampal slices from mutant mice show a severe deficit in LTD and depotentiation at the Schaffer collateral-CA1 synapse. This defect is also evident at the lateral perforant path-dentate granule cell synapse in RI beta mutant mice. Despite a compensatory increase in the related RI alpha protein and a lack of detectable changes in total PKA activity, the hippocampal function in these mice is not rescued, suggesting a unique role for RI beta. Since the late phase of CA1 LTP also requires PKA but is normal in RI beta mutant mice, our data further suggest that different forms of synaptic plasticity are likely to employ different combinations of regulatory and catalytic subunits. IMAGES:

环磷酸腺苷依赖性蛋白激酶（cAMP-dependent protein kinase, PKA）已被证实可在海马体的长时程增强（long-term potentiation, LTP）中发挥关键作用，但目前学界对于PKA在长时程抑制（long-term depression, LTD）中的功能仍知之甚少。本研究结合药理学与遗传学研究手段，证实PKA活性对于同源突触长时程抑制及去增强（depotentiation）均为必需，且I型调节亚基的特定神经元亚型（RIβ）发挥不可或缺的作用。我们通过胚胎干细胞基因打靶技术，构建了RIβ编码基因携带功能缺失突变的小鼠模型。突变小鼠的海马脑片在施弗侧枝-CA1突触处，出现严重的长时程抑制与去增强缺陷；该缺陷在RIβ突变小鼠的外侧穿通通路-齿状颗粒细胞突触处同样可见。尽管相关的RIα蛋白出现代偿性升高，且总PKA活性未出现可检测到的变化，但这些小鼠的海马体功能并未得到挽救，这提示RIβ具有独特的功能角色。由于CA1区长时程增强的晚期时相同样依赖PKA，但在RIβ突变小鼠中表现正常，本研究数据进一步表明，不同形式的突触可塑性可能采用不同的调节亚基与催化亚基组合模式。图像：