Jefferys J G, Whittington M A
Department of Physiology, University of Birmingham, UK.
Epilepsy Res. 1996 Dec;26(1):59-66. doi: 10.1016/s0920-1211(96)00040-x.
Blocking inhibition provides one of the most common experimental means of triggering epileptic activity in hippocampus and neocortex. However, it has proved much more difficult to show that chronic models of epilepsies are due to disinhibition. One problem is knowing how much inhibition needs to be blocked to provide a sufficient mechanism for epileptic activity. We have found that inhibitory (GABAA) transmission, estimated from evoked monosynaptic IPSCs, must be reduced to 17% of their control amplitude (by 4-7 microM bicuculline) before hippocampal slices generate all-or-none epileptic discharges. Similar estimates of inhibition in chronic epileptic foci induced by intrahippocampal injection of tetanus toxin showed that monosynaptic IPSCs dropped to 10% of control in the injected hippocampus during the first 2 weeks after injection. At all other stages of the active epileptic foci in the two hippocampi the reduction in IPSCs was not alone sufficient for epileptic activity; at 4-6 weeks IPSCs were normal despite continued epileptic activity. One likely mechanism for the late epileptic activity is a reduction of either the intrinsic excitability, or the synaptic excitation, of inhibitory interneurons so they fail to be recruited normally. Alternative mechanisms include the formation of new excitatory connections, as found at modest levels in the dentate gyrus. Several mechanisms may play a part in chronic foci such as those induced by tetanus toxin, either acting together, or sequentially during the progression of the epileptic focus.
阻断抑制作用是引发海马体和新皮质癫痫活动最常见的实验手段之一。然而，要证明慢性癫痫模型是由去抑制作用引起的却困难得多。一个问题是要知道需要阻断多少抑制作用才能为癫痫活动提供充分的机制。我们发现，根据诱发的单突触抑制性突触后电流（IPSCs）估算，抑制性（GABAA）传递必须降至其对照幅度的17%（通过4 - 7微摩尔荷包牡丹碱），海马体切片才会产生全或无的癫痫放电。对海马体内注射破伤风毒素诱导的慢性癫痫病灶中抑制作用的类似估算表明，在注射后的前两周内，注射侧海马体中的单突触IPSCs降至对照的10%。在两个海马体中活跃癫痫病灶的所有其他阶段，IPSCs的减少本身并不足以引发癫痫活动；在4 - 6周时，尽管癫痫活动持续，IPSCs仍正常。晚期癫痫活动的一个可能机制是抑制性中间神经元的内在兴奋性或突触兴奋性降低，导致它们无法正常被激活。其他机制包括形成新的兴奋性连接，如在齿状回中适度水平发现的那样。几种机制可能在诸如破伤风毒素诱导的慢性病灶中起作用，它们在癫痫病灶进展过程中可能共同作用或相继起作用。
