Makhinson M, Opazo P, Carlisle H J, Godsil B, Grant S G N, O'Dell T J
Department of Physiology, David Geffen School of Medicine at UCLA, 53-231 Center for Health Sciences, Box 951751, Los Angeles, CA 90095, USA.
Neuroscience. 2006 Jun 30;140(2):415-31. doi: 10.1016/j.neuroscience.2006.02.018. Epub 2006 Mar 23.
At excitatory synapses onto hippocampal CA1 pyramidal cells, activation of cyclic AMP-dependent protein kinase and subsequent down-regulation of protein phosphatases has a crucial role in the induction of long-term potentiation by low-frequency patterns of synaptic stimulation. Because the second messenger cyclic guanosine 3',5'monophosphate can regulate the activity of different forms of the cyclic AMP degrading enzyme phosphodiesterase, we examined whether increases in cyclic guanosine 3',5'monophosphate can modulate long-term potentiation induction in the mouse hippocampal CA1 region through effects on cyclic AMP signaling. Using the cyclic guanosine 3',5'monophosphate-specific phosphodiesterase inhibitor zaprinast or the nitric oxide donor S-nitroso-D,L-penicillamine to elevate cyclic guanosine 3',5'monophosphate levels we found that increases in cyclic guanosine 3',5'monophosphate strongly inhibit the induction of long-term potentiation by low-frequency patterns of synaptic stimulation where protein kinase A activation is required for long-term potentiation induction. In contrast, zaprinast and S-nitroso-D,L-penicillamine had no effect on the induction of long-term potentiation by high-frequency patterns of synaptic stimulation that induce long-term potentiation in a protein kinase A-independent manner. Directly activating protein kinase A with the phosphodiesterase-resistant cyclic AMP analog 8-Br-cAMP, blocking all phosphodiesterases with 3-isobutyl-1-methylxanthine, or inhibiting protein phosphatases rescued long-term potentiation induction in zaprinast-treated slices. Together, these results suggest that increases in cyclic guanosine 3',5'monophosphate inhibit long-term potentiation by activating phosphodiesterases that interfere with the protein kinase A-mediated suppression of protein phosphatases needed for long-term potentiation induction. Consistent with the notion that this cyclic guanosine 3',5'monophosphate-mediated inhibitory pathway is recruited by some patterns of synaptic activity, blocking cyclic guanosine 3',5'monophosphate production strongly facilitated the induction of long-term potentiation by long trains of theta-frequency synaptic stimulation. Together, our results indicate that increases in cyclic guanosine 3',5'monophosphate can act as a long-term potentiation suppressor mechanism that selectively constrains the induction of protein kinase A-dependent forms of long-term potentiation induced by low-frequency patterns of synaptic stimulation.
在海马CA1区锥体细胞的兴奋性突触上，环磷酸腺苷依赖性蛋白激酶的激活以及随后蛋白磷酸酶的下调，在低频突触刺激诱导长时程增强中起关键作用。由于第二信使环磷酸鸟苷可调节环磷酸腺苷降解酶磷酸二酯酶不同形式的活性，我们研究了环磷酸鸟苷的增加是否能通过影响环磷酸腺苷信号传导来调节小鼠海马CA1区的长时程增强诱导。使用环磷酸鸟苷特异性磷酸二酯酶抑制剂扎普司特或一氧化氮供体S-亚硝基-D,L-青霉胺来提高环磷酸鸟苷水平，我们发现环磷酸鸟苷的增加强烈抑制低频突触刺激诱导的长时程增强，而这种低频突触刺激诱导长时程增强需要蛋白激酶A的激活。相反，扎普司特和S-亚硝基-D,L-青霉胺对高频突触刺激诱导的长时程增强没有影响，高频突触刺激以不依赖蛋白激酶A的方式诱导长时程增强。用抗磷酸二酯酶的环磷酸腺苷类似物8-溴环磷酸腺苷直接激活蛋白激酶A，用3-异丁基-1-甲基黄嘌呤阻断所有磷酸二酯酶，或抑制蛋白磷酸酶可挽救扎普司特处理切片中的长时程增强诱导。总之，这些结果表明，环磷酸鸟苷的增加通过激活磷酸二酯酶来抑制长时程增强，这些磷酸二酯酶会干扰蛋白激酶A介导的对长时程增强诱导所需蛋白磷酸酶的抑制。与这种环磷酸鸟苷介导的抑制途径被某些突触活动模式所激活的观点一致，阻断环磷酸鸟苷的产生强烈促进了由长时间的θ频率突触刺激诱导的长时程增强。总之，我们的结果表明，环磷酸鸟苷的增加可作为一种长时程增强抑制机制，选择性地限制由低频突触刺激诱导的蛋白激酶A依赖性长时程增强的诱导。
