Postsynaptic application of a peptide inhibitor of cAMP-dependent protein kinase blocks expression of long-lasting synaptic potentiation in hippocampal neurons
Postsynaptic application of a peptide inhibitor of cAMP-dependent protein kinase blocks expression of long-lasting synaptic potentiation in hippocampal neurons
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DOI：
10.1523/jneurosci.23-04-01142.2003
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发表时间：
2003-02-15
影响因子：
5.3
通讯作者：
Nguyen, PV
中科院分区：
文献类型：
--
作者：
Duffy, SN;Nguyen, PV
多次高频突触刺激会引起海马 CA1 区突触传递的长期增强 (LTP)，这与海马长期记忆相关，并且需要激活 cAMP 依赖性蛋白激酶 (PKA)。为了评估突触后 PKA 是否是 LTP 表达所必需的，我们在突触后输注 PKA 细胞非渗透性调节剂期间，对小鼠海马切片 CA1 锥体神经元进行了长时间的全细胞电压钳记录。重复刺激 Schaffer 侧支通路（每 5 分钟间隔 4 次 100 Hz 序列）可增加突触诱发 EPSC 长达 2 小时。突触后输注细胞渗透性 PKA 抑制剂 (Rp-cAMPS) 或细胞非渗透性 PKA 抑制剂 (PKI6-22) 不会改变强直后峰值增强，但会导致 EPSC 在 1.5 小时内显着衰减至强直前振幅。相比之下，突触后输注 PKI6-22 并没有改变由单个 100 Hz 序列引起的更温和、衰减的 LTP 形式。配对脉冲促进在 LTP 的大部分持续时间内没有变化，这表明突触后机制（包括 PKA 激活）参与了多序列刺激诱导的 LTP 表达。将 PKA 催化亚基 (Calpha) 的组成型活性亚型突触后注入 CA1 锥体神经元可增加 EPSC 的大小，从而引发持久的突触促进。因此，模拟突触后 CA1 锥体神经元中 PKA 的激活足以诱导持续的突触促进。突触后 PKA 的激活对于 CA1 锥体神经元中 LTP 的表达是必要的，并且足以启动持续的突触促进。
Multiple trains of high-frequency synaptic stimulation evoke long-term potentiation (LTP) of synaptic transmission in hippocampal area CA1, which has been correlated with hippocampal long-term memory and requires the activation of cAMP-dependent protein kinase (PKA). To assess whether postsynaptic PKA is necessary for the expression of LTP, we made prolonged whole-cell voltage-clamp recordings from CA1 pyramidal neurons in mouse hippocampal slices during postsynaptic infusion of cell-impermeant modulators of PKA. Repeated stimulation (four 100 Hz trains at 5 min intervals) of the Schaffer collateral pathway increased synaptically evoked EPSCs for up to 2 hr. The postsynaptic infusion of either a cell-permeant PKA inhibitor (Rp-cAMPS) or a cell-impermeant PKA inhibitor (PKI6-22) did not alter post-tetanic peak potentiation, but it caused significant decay of EPSCs to pretetanization amplitudes within 1.5 hr. In contrast, postsynaptic infusion of PKI6-22 did not alter a more modest, decaying form of LTP evoked by a single 100 Hz train. Paired-pulse facilitation was unchanged during most of the duration of LTP, suggesting that postsynaptic mechanisms, including PKA activation, are involved in the expression of LTP induced by multitrain stimulation. The postsynaptic infusion of a constitutively active isoform of the PKA catalytic subunit (Calpha) into CA1 pyramidal neurons increased EPSC sizes to elicit long-lasting synaptic facilitation. Thus, mimicking the activation of PKA in postsynaptic CA1 pyramidal neurons is sufficient for inducing persistent synaptic facilitation. Activation of apostsynaptic PKA is necessary for the expression of LTP in CA1 pyramidal neurons and is sufficient for initiating persistent synaptic facilitation.