Neuromed IRCCS, Pozzilli, Italy.
Department of Neurosurgery, Sapienza University of Rome, Rome, Italy.
Epilepsia. 2018 Feb;59(2):449-459. doi: 10.1111/epi.13991. Epub 2017 Dec 28.
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in adult central nervous system, and profound alterations of GABA receptor functions are linked to temporal lobe epilepsy (TLE). Here we describe the functional relationships between GABA receptors type B (GABA R) and type A (GABA R) in human temporal cortex and how TLE affects this aspect of GABAergic signaling.
Miniature inhibitory postsynaptic currents (mIPSCs) were recorded by patch-clamp techniques from human L5 pyramidal neurons in slices from temporal cortex tissue obtained from surgery.
We describe a constitutive functional crosstalk between GABA Rs and GABA Rs in human temporal layer 5 pyramidal neurons, which is lost in epileptic tissues. The activation of GABA Rs by baclofen, in addition to the expected reduction of mIPSC frequency, produced, in cortex of nonepileptic patients, the prolongation of mIPSC rise and decay times, thus increasing the inhibitory net charge associated with a single synaptic event. Block of K channels did not prevent the increase of decay time and charge. Protein kinase A (PKA) blocker KT5720 and pertussis toxin inhibited the action of baclofen, whereas 8Br-cAMP mimicked the GABA R action. The same GABA R-mediated modulation of GABA Rs was observed in pyramidal neurons of rat temporal cortex, with both PKA and PKC involved in the process. In cortices from TLE patients and epileptic rats, baclofen lost its ability to modulate mIPSCs.
Our results highlight the association of TLE with functional changes of GABAergic signaling that may be related to seizure propagation, and suggest that the selective activation of a definite subset of nonpresynaptic GABA Rs may be therapeutically useful in TLE.
γ-氨基丁酸（GABA）是成人中枢神经系统中的主要抑制性神经递质，GABA 受体功能的深刻改变与颞叶癫痫（TLE）有关。在这里，我们描述了人类颞叶皮质中 GABA 受体 B 型（GABA R）和 A 型（GABA R）之间的功能关系，以及 TLE 如何影响 GABA 能信号传递的这一方面。
通过在来自颞叶皮质组织的切片上进行膜片钳技术记录，从小脑锥体神经元中记录微小抑制性突触后电流（mIPSCs）。
我们描述了在人类颞叶 5 层锥体神经元中存在 GABA Rs 和 GABA Rs 之间的组成性功能串扰，而在癫痫组织中这种串扰丢失。用巴氯芬激活 GABA Rs，除了预期的降低 mIPSC 频率外，还会在无癫痫患者的皮质中延长 mIPSC 的上升和下降时间，从而增加与单个突触事件相关的抑制净电荷。钾通道阻断剂不能防止衰减时间和电荷的增加。蛋白激酶 A（PKA）阻断剂 KT5720 和百日咳毒素抑制了巴氯芬的作用，而 8Br-cAMP 模拟了 GABA R 的作用。在大鼠颞叶皮质的锥体神经元中也观察到了相同的 GABA R 介导的 GABA Rs 调制，其中 PKA 和 PKC 均参与了该过程。在 TLE 患者和癫痫大鼠的皮质中，巴氯芬失去了调制 mIPSCs 的能力。
我们的结果强调了 TLE 与 GABA 能信号传递的功能变化有关，这可能与癫痫发作的传播有关，并表明选择性激活特定的非突触 GABA Rs 子集可能对 TLE 具有治疗意义。
