Patrylo P R, Spencer D D, Williamson A
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
J Neurophysiol. 2001 Apr;85(4):1533-42. doi: 10.1152/jn.2001.85.4.1533.
In vivo dialysis and in vitro electrophysiological studies suggest that GABA uptake is altered in the dentate gyrus of human temporal lobe epileptics characterized with mesial temporal sclerosis (MTLE). Concordantly, anatomical studies have shown that the pattern of GABA-transporter immunoreactivity is also altered in this region. This decrease in GABA uptake, presumably due to a change in the GABA transporter system, may help preserve inhibitory tone interictally. However, transporter reversal can also occur under several conditions, including elevations in [K(+)]o, which occurs during seizures. Thus GABA transporters could contribute to seizure termination and propagation through heterotransport. To test whether GABA transport is compromised in both the forward (uptake) and reverse (heterotransport) direction in the sclerotic epileptic dentate gyrus, the physiological effects of microapplied GABA and nipecotic acid (NPA; a compound that induces heterotransport) were examined in granule cells in hippocampal slices from kainate (KA)-induced epileptic rats and patients with temporal lobe epilepsy (TLE). GABA- and NPA-induced responses were prolonged in granule cells from epileptic rats versus controls (51.3 and 31.3% increase, respectively) while the conductance change evoked with NPA microapplication was reduced by 40%. Furthermore the ratio of GABA/NPA conductance, but not duration, was significantly >1 in epileptic rats but not controls, suggesting a compromise in transporter function in both directions. Similar changes were observed in tissue resected from epileptic patients with medial temporal sclerosis but not in those without the anatomical changes associated with MTLE. These data suggest that the GABA transporter system is functionally compromised in both the forward and reverse directions in the dentate gyrus of chronically epileptic tissue characterized by mesial temporal sclerosis. This alteration may enhance inhibitory tone interically yet be permissive for seizure propagation due to a decreased probability for GABA heterotransport during seizures.
体内透析和体外电生理研究表明，在以内侧颞叶硬化（MTLE）为特征的人类颞叶癫痫患者的齿状回中，γ-氨基丁酸（GABA）摄取发生改变。与此一致的是，解剖学研究表明，该区域GABA转运体免疫反应性模式也发生了改变。GABA摄取的这种减少，可能是由于GABA转运体系统的变化，可能有助于在发作间期维持抑制性张力。然而，在包括发作期间细胞外钾离子浓度升高在内的几种情况下，转运体也会发生逆转。因此，GABA转运体可能通过异向转运参与癫痫发作的终止和传播。为了测试硬化性癫痫齿状回中GABA转运在正向（摄取）和反向（异向转运）方向是否均受损，研究人员在来自 kainate（KA）诱导的癫痫大鼠和颞叶癫痫（TLE）患者的海马切片颗粒细胞中，检测了微量应用GABA和哌啶酸（NPA；一种诱导异向转运的化合物）的生理效应。与对照组相比，癫痫大鼠颗粒细胞中GABA和NPA诱导的反应延长（分别增加51.3%和31.3%），而微量应用NPA引起的电导变化降低了4⃣️0⃣️%。此外，癫痫大鼠而非对照组中，GABA/NPA电导比值（而非持续时间）显著大于1，这表明两个方向的转运体功能均受损。在内侧颞叶硬化的癫痫患者切除的组织中观察到类似变化，但在没有与MTLE相关解剖学变化的患者中未观察到。这些数据表明，在以内侧颞叶硬化为特征的慢性癫痫组织的齿状回中，GABA转运体系统在正向和反向方向上功能均受损。这种改变可能在发作间期增强抑制性张力，但由于发作期间GABA异向转运的可能性降低，可能会促进癫痫发作的传播。
