Xu C, Liu Q-Y, Alkon D L
Blanchette Rockefeller Neurosciences Institute, Morgantown, WV 26506, United States of America.
Blanchette Rockefeller Neurosciences Institute, Morgantown, WV 26506, United States of America.
Neuroscience. 2014 May 30;268:75-86. doi: 10.1016/j.neuroscience.2014.03.008. Epub 2014 Mar 15.
Bryostatin-1, a potent agonist of protein kinase C (PKC), has recently been found to enhance spatial learning and long-term memory in rats, mice, rabbits and the nudibranch Hermissenda, and to exert profound neuroprotective effects on Alzheimer's disease (AD) in transgenic mice. However, details of the mechanistic effects of bryostatin on learning and memory remain unclear. To address this issue, whole-cell recording, a dual-recording approach and extracellular recording techniques were performed on young (2-4months) Brown-Norway rats. We found that bath-applied bryostatin-1 significantly increased the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). The firing rate of GABAergic interneurons significantly was also increased as recorded with a loosely-attached extracellular recording configuration. Simultaneous recordings from communicating cell pairs of interneuron and pyramidal neuron revealed unique activity-dependent properties of GABAergic synapses. Furthermore, the bryostatin-induced increase of the frequency and amplitude of IPSCs was blocked by methionine enkephalin which selectively suppressed the excitability of interneurons. Pretreatment with RO-32-0432, a relatively specific PKCα antagonist, blocked the effect of bryostatin on sIPSCs. Finally, bryostatin increased paired-pulse ratio of GABAergic synapses that lasted for at least 20min while pretreatment with RO-32-0432 significantly reduced the ratio. In addition, 8-[2-(2-pentyl-cyclopropylmethl)-cyclopropyl]-octanoic acid (DCP-LA), a selective PKCε activator, also increased the frequency and amplitude of sIPSCs. Taken together, these results suggest that bryostatin enhances GABAergic neurotransmission in pyramidal neurons by activating the PKCα & ε-dependent pathway and by a presynaptic mechanism with excitation of GABAergic interneurons. These effects of bryostatin on GABAergic transmissions and modifiability may contribute to the improvement of learning and memory previously observed to be induced by bryostatin.
苔藓抑素-1是一种强效的蛋白激酶C（PKC）激动剂，最近发现它能增强大鼠、小鼠、兔子和海蛞蝓Hermissenda的空间学习和长期记忆，并对转基因小鼠的阿尔茨海默病（AD）产生深远的神经保护作用。然而，苔藓抑素对学习和记忆的作用机制细节仍不清楚。为了解决这个问题，我们对年轻（2 - 4个月）的布朗挪威大鼠进行了全细胞记录、双记录方法和细胞外记录技术。我们发现，浴加苔藓抑素-1显著增加了自发性抑制性突触后电流（sIPSCs）的频率和幅度。用松散附着的细胞外记录配置记录时，GABA能中间神经元的放电率也显著增加。对中间神经元和锥体神经元的通信细胞对进行同步记录揭示了GABA能突触独特的活动依赖性特性。此外，甲硫氨酸脑啡肽阻断了苔藓抑素诱导的IPSCs频率和幅度的增加，甲硫氨酸脑啡肽选择性地抑制了中间神经元的兴奋性。用相对特异性的PKCα拮抗剂RO - 32 - 0432预处理可阻断苔藓抑素对sIPSCs的作用。最后，苔藓抑素增加了GABA能突触的配对脉冲比率，该比率持续至少20分钟，而用RO - 32 - 0432预处理显著降低了该比率。此外，选择性PKCε激活剂8 - [2 - (2-戊基-环丙基甲基)-环丙基]-辛酸（DCP - LA）也增加了sIPSCs的频率和幅度。综上所述，这些结果表明，苔藓抑素通过激活PKCα和ε依赖性途径以及通过GABA能中间神经元兴奋的突触前机制增强锥体神经元中的GABA能神经传递。苔藓抑素对GABA能传递和可塑性的这些作用可能有助于改善先前观察到的由苔藓抑素诱导的学习和记忆。
