Tosetti P, Ferrand N, Colin-Le Brun I, Gaïarsa J L
Institut de Génomique Fonctionnelle, CNRS UMR5203/INSERM U661/UM1/UM2, Montpellier, France.
J Physiol. 2005 Nov 1;568(Pt 3):951-66. doi: 10.1113/jphysiol.2005.094631. Epub 2005 Aug 11.
GABA(B) receptor (GABA(B)R)-mediated presynaptic inhibition regulates neurotransmitter release from synaptic terminals. In the neonatal hippocampus, GABA(B)R activation reduces GABA release and terminates spontaneous network discharges called giant depolarizing potentials (GDPs). Blocking GABA(B)Rs transforms GDPs into longer epileptiform discharges. Thus, GABA(B)R-mediated presynaptic inhibition of GABA release (GABA auto-inhibition) controls both spontaneous network activity and excitability in the developing hippocampus. Here we show that extensive release of endogenous GABA during epileptiform activity impairs GABA auto-inhibition, but not GABA(B)R-mediated inhibition of glutamate release, leading to hyperexcitability of the neonatal hippocampal network. Paired-pulse depression of GABA release (PPD) and heterosynaptic depression of glutamate release were used to monitor the efficacy of presynaptic GABA(B)R-mediated inhibition in slices. PPD, but not heterosynaptic depression, was dramatically reduced after potassium (K+)-induced ictal-like discharges (ILDs), suggesting a selective impairment of GABA(B)R-dependent presynaptic inhibition of GABAergic terminals. Impairing GABA auto-inhibition induced a 44% increase in GDP width and the appearance of pathological network discharges. Preventing GABA-induced activation of GABA(B)Rs during ILDs avoided PPD loss and most modifications of the network activity. In contrast, a partial block of GABA(B)Rs induced network discharges strikingly similar to those observed after K+-driven ILDs. Finally, neither loss of GABA auto-inhibition nor network hyperexcitability could be observed following synchronous release of endogenous GABA in physiological conditions (during GDPs at 1 Hz). Thus, epileptiform activity was instrumental to impair GABA(B)R-dependent presynaptic inhibition of GABAergic terminals. In conclusion, our results indicate that endogenous GABA released during epileptiform activity can reduce GABA auto-inhibition and trigger pathological network discharges in the newborn rat hippocampus. Such functional impairment may play a role in acute post-seizure plasticity.
γ-氨基丁酸B型受体（GABA(B)R）介导的突触前抑制调节神经递质从突触终末的释放。在新生海马体中，GABA(B)R激活会减少GABA释放，并终止称为巨大去极化电位（GDPs）的自发网络放电。阻断GABA(B)Rs会将GDPs转变为更长的癫痫样放电。因此，GABA(B)R介导的GABA释放的突触前抑制（GABA自身抑制）控制着发育中海马体的自发网络活动和兴奋性。在此我们表明，癫痫样活动期间内源性GABA的大量释放会损害GABA自身抑制，但不会损害GABA(B)R介导的谷氨酸释放抑制，从而导致新生海马体网络的过度兴奋。GABA释放的配对脉冲抑制（PPD）和谷氨酸释放的异突触抑制被用于监测海马切片中突触前GABA(B)R介导的抑制效果。在钾离子（K+）诱导的癫痫样放电（ILDs）后，PPD显著降低，但异突触抑制未受影响，这表明GABA能终末的GABA(B)R依赖性突触前抑制受到选择性损害。损害GABA自身抑制会使GDP宽度增加44%，并出现病理性网络放电。在ILDs期间阻止GABA诱导的GABA(B)Rs激活可避免PPD丧失以及网络活动的大多数改变。相反，GABA(B)Rs的部分阻断会诱导出与K+驱动的ILDs后观察到的网络放电极为相似的放电。最后，在生理条件下（1赫兹的GDPs期间）内源性GABA同步释放后，未观察到GABA自身抑制丧失或网络过度兴奋。因此，癫痫样活动有助于损害GABA能终末的GABA(B)R依赖性突触前抑制。总之，我们的结果表明，癫痫样活动期间释放的内源性GABA可降低GABA自身抑制，并在新生大鼠海马体中引发病理性网络放电。这种功能损害可能在急性发作后可塑性中起作用。
