Morrisett R A, Mott D D, Lewis D V, Swartzwelder H S, Wilson W A
Department of Medicine (Neurology), Duke University Medical Center, Durham, North Carolina 27710.
J Neurosci. 1991 Jan;11(1):203-9. doi: 10.1523/JNEUROSCI.11-01-00203.1991.
GABA receptor regulation of NMDA-receptor-mediated synaptic responses was studied in area CA1 of the rat hippocampus using extracellular and intracellular recording techniques. Picrotoxin (PTX) was used to suppress GABAA inhibition and 6,7-dinitroquinoxaline-2,3-dione (DNQX) was used to suppress non-NMDA receptor-mediated responses. In this manner, we were able to avoid the complicating factors caused by potentials induced by other excitatory and inhibitory amino acid receptors. Under these conditions, large NMDA-receptor-mediated EPSPs were observed. When paired stimuli were given at interstimulus intervals from 100 to 400 msec, powerful inhibition of the second response was observed. This inhibition was reversed by the GABAB antagonists phaclofen and 2-hydroxy-saclofen; it was also depressed by removal of Mg2+ from the bath. Examination of non-NMDA receptor-mediated synaptic responses (determined in the presence of D-2-amino-5-phosphonovalerate and PTX) showed no such inhibition, thereby supporting the hypothesis that GABAB inhibition of NMDA EPSPs is postsynaptic. This difference in paired-pulse inhibition of NMDA and non-NMDA EPSPs leads us to conclude that there was no evidence of GABAB-mediated presynaptic inhibition of excitatory transmitter release. Intracellular recordings in the presence of DNQX and PTX revealed a phaclofen-sensitive late IPSP that correlated in time with the period of inhibition of NMDA responses. Taken together, these data suggest that paired-pulse-inhibition of NMDA responses is produced by a GABAB-receptor-mediated hyperpolarization of the postsynaptic membrane, causing an enhanced block of the NMDA channels by Mg2+. Regulation of NMDA-mediated synaptic responses by GABAB receptors constitutes a powerful mechanism for control of a major excitatory system in hippocampal pyramidal cells.
采用细胞外和细胞内记录技术，在大鼠海马CA1区研究了GABA受体对NMDA受体介导的突触反应的调节作用。使用印防己毒素（PTX）抑制GABAA抑制作用，使用6,7 - 二硝基喹喔啉 - 2,3 - 二酮（DNQX）抑制非NMDA受体介导的反应。通过这种方式，我们能够避免由其他兴奋性和抑制性氨基酸受体诱导的电位所引起的复杂因素。在这些条件下，观察到了大的NMDA受体介导的兴奋性突触后电位（EPSP）。当以100至400毫秒的刺激间隔给予配对刺激时，观察到对第二个反应的强烈抑制。这种抑制作用可被GABAB拮抗剂巴氯芬和2 - 羟基 - 巴氯芬逆转；通过从浴槽中去除Mg2+也可使其减弱。对非NMDA受体介导的突触反应（在D - 2 - 氨基 - 5 - 磷酸戊酸和PTX存在下测定）的检查未显示出这种抑制作用，从而支持了GABAB对NMDA EPSP的抑制作用是突触后性抑制的假说。NMDA和非NMDA EPSP的配对脉冲抑制的这种差异使我们得出结论，没有证据表明存在GABAB介导的兴奋性递质释放的突触前抑制。在DNQX和PTX存在下的细胞内记录显示出一种对巴氯芬敏感的晚期抑制性突触后电位（IPSP），其在时间上与NMDA反应的抑制期相关。综上所述，这些数据表明，NMDA反应的配对脉冲抑制是由GABAB受体介导的突触后膜超极化产生的，导致Mg2+对NMDA通道的阻断增强。GABAB受体对NMDA介导的突触反应的调节构成了控制海马锥体细胞中主要兴奋性系统的强大机制。
