Brown G P, Blitzer R D, Connor J H, Wong T, Shenolikar S, Iyengar R, Landau E M
Departments of Pharmacology and Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA.
J Neurosci. 2000 Nov 1;20(21):7880-7. doi: 10.1523/JNEUROSCI.20-21-07880.2000.
Long-term potentiation (LTP) can be induced in the Schaffer collateral-->CA1 synapse of hippocampus by stimulation in the theta frequency range (5-12 Hz), an effect that depends on activation of the cAMP pathway. We investigated the mechanisms of the cAMP contribution to this form of LTP in the rat hippocampal slice preparation. theta pulse stimulation (TPS; 150 stimuli at 10 Hz) by itself did not induce LTP, but the addition of either the beta-adrenergic agonist isoproterenol or the cAMP analog 8-bromo-cAMP (8-Br-cAMP) enabled TPS-induced LTP. The isoproterenol effect was blocked by postsynaptic inhibition of cAMP-dependent protein kinase. Several lines of evidence indicated that cAMP enabled LTP by blocking postsynaptic protein phosphatase-1 (PP1). Activators of the cAMP pathway reduced PP1 activity in the CA1 region and increased the active form of inhibitor-1, an endogenous inhibitor of PP1. Postsynaptic injection of activated inhibitor-1 mimicked the LTP-enabling effect of cAMP pathway stimulation. TPS evoked complex spiking when isoproterenol was present. However, complex spiking was not sufficient to enable TPS-induced LTP, which additionally required the inhibition of postsynaptic PP1. PP1 inhibition seems to promote the activation of Ca(2+)/calmodulin-dependent protein kinase (CaMKII), because (1) a CaMKII inhibitor blocked the induction of LTP by TPS paired with either isoproterenol or activated inhibitor-1 and (2) CaMKII in area CA1 was activated by the combination of TPS and 8-Br-cAMP but not by either stimulus alone. These results indicate that the cAMP pathway enables TPS-induced LTP by inhibiting PP1, thereby enhancing Ca(2+)-independent CaMKII activity.
在海马体的谢弗侧支-海马体1区（Schaffer collateral-->CA1）突触中，通过θ频率范围（5 - 12赫兹）的刺激可诱导长时程增强（LTP），该效应依赖于环磷酸腺苷（cAMP）信号通路的激活。我们在大鼠海马切片标本中研究了cAMP对这种形式的LTP的作用机制。θ脉冲刺激（TPS；10赫兹下150次刺激）本身不会诱导LTP，但添加β-肾上腺素能激动剂异丙肾上腺素或cAMP类似物8-溴-cAMP（8-Br-cAMP）可使TPS诱导LTP。异丙肾上腺素的作用可被cAMP依赖性蛋白激酶的突触后抑制所阻断。多条证据表明，cAMP通过阻断突触后蛋白磷酸酶-1（PP1）来实现LTP。cAMP信号通路的激活剂降低了海马体1区的PP1活性，并增加了内源性PP1抑制剂-1的活性形式。突触后注射激活的抑制剂-1模拟了cAMP信号通路刺激的LTP促进作用。当存在异丙肾上腺素时，TPS诱发复合锋电位。然而，复合锋电位不足以使TPS诱导LTP，还需要抑制突触后PP1。PP1抑制似乎促进了钙/钙调蛋白依赖性蛋白激酶（CaMKII）的激活，因为（1）CaMKII抑制剂阻断了TPS与异丙肾上腺素或激活的抑制剂-1配对诱导的LTP，并且（2）海马体1区的CaMKII通过TPS和8-Br-cAMP的联合激活，但单独的任何一种刺激都不能激活。这些结果表明，cAMP信号通路通过抑制PP1来实现TPS诱导的LTP，从而增强不依赖钙的CaMKII活性。
