Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratories, Prince of Wales Road, Exeter EX4 4PS, UK.
Eli Lilly UK, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK.
J Physiol. 2018 Jun;596(11):2251-2266. doi: 10.1113/JP275871. Epub 2018 Apr 25.
The medial entorhinal cortex (mEC) has an important role in initiation and propagation of seizure activity. Several anatomical relationships exist in neurophysiological properties of mEC neurons; however, in the context of hyperexcitability, previous studies often considered it as a homogeneous structure. Using multi-site extracellular recording techniques, ictal-like activity was observed along the dorso-ventral axis of the mEC in vitro in response to various ictogenic stimuli. This originated predominantly from ventral areas, spreading to dorsal mEC with a surprisingly slow velocity. Modulation of inhibitory tone was capable of changing the slope of ictal initiation, suggesting seizure propagation behaviours are highly dependent on levels of GABAergic function in this region. A distinct disinhibition model also showed, in the absence of inhibition, a prevalence for interictal-like initiation in ventral mEC, reflecting the intrinsic differences in mEC neurons. These findings suggest the ventral mEC is more prone to hyperexcitable discharge than the dorsal mEC, which may be relevant under pathological conditions.
The medial entorhinal cortex (mEC) has an important role in the generation and propagation of seizure activity. The organization of the mEC is such that a number of dorso-ventral relationships exist in neurophysiological properties of neurons. These range from intrinsic and synaptic properties to density of inhibitory connectivity. We examined the influence of these gradients on generation and propagation of epileptiform activity in the mEC. Using a 16-shank silicon probe array to record along the dorso-ventral axis of the mEC in vitro, we found 4-aminopyridine application produces ictal-like activity originating predominantly in ventral areas. This activity spreads to dorsal mEC at a surprisingly slow velocity (138 μm s ), while cross-site interictal-like activity appeared relatively synchronous. We propose that ictal propagation is constrained by differential levels of GABAergic control since increasing (diazepam) or decreasing (Ro19-4603) GABA receptor activation, respectively, reduced or increased the slope of ictal initiation. The observation that ictal activity is predominately generated in ventral mEC was replicated using a separate 0-Mg model of epileptiform activity in vitro. By using a distinct disinhibition model (co-application of kainate and picrotoxin) we show that additional physiological features (for example intrinsic properties of mEC neurons) still produce a prevalence for interictal-like initiation in ventral mEC. These findings suggest that the ventral mEC is more likely to initiate hyperexcitable discharges than the dorsal mEC, and that seizure propagation is highly dependent on levels of GABAergic expression across the mEC.
内侧嗅皮层（mEC）在癫痫发作活动的起始和传播中具有重要作用。mEC 神经元的神经生理特性存在多种解剖关系；然而，在过度兴奋的情况下，先前的研究通常将其视为同质结构。使用多部位细胞外记录技术，在体外对 mEC 的背腹轴上的各种致痫刺激进行观察，发现癫痫样活动。该活动主要起源于腹侧区域，以惊人的慢速度传播到背侧 mEC。抑制性张力的调节能够改变癫痫发作起始的斜率，表明癫痫传播行为高度依赖于该区域 GABA 能功能的水平。另一种明显的去抑制模型也表明，在没有抑制的情况下，腹侧 mEC 中存在癫痫样起始的优势，这反映了 mEC 神经元内在的差异。这些发现表明，腹侧 mEC 比背侧 mEC 更容易发生过度兴奋放电，这在病理条件下可能是相关的。
内侧嗅皮层（mEC）在癫痫发作活动的产生和传播中具有重要作用。mEC 的组织方式使得神经元的神经生理特性存在许多背腹关系。这些关系范围从内在和突触特性到抑制性连接的密度。我们研究了这些梯度对 mEC 中癫痫样活动的产生和传播的影响。使用 16 个硅探针阵列在体外记录 mEC 的背腹轴，我们发现 4-氨基吡啶的应用产生主要起源于腹侧区域的癫痫样活动。该活动以惊人的慢速度（138 μm s）传播到背侧 mEC，而跨部位的癫痫样活动则相对同步。我们提出，癫痫发作的传播受到 GABA 能控制水平的差异的限制，因为增加（地西泮）或减少（Ro19-4603）GABA 受体激活分别减少或增加了癫痫发作起始的斜率。在体外使用另一种 0-Mg 癫痫样活动的分离抑制模型复制了腹侧 mEC 中主要产生癫痫发作活动的观察结果。通过使用另一种明显的去抑制模型（共同应用 kainate 和 picrotoxin），我们表明其他生理特征（例如 mEC 神经元的内在特性）仍然导致腹侧 mEC 中癫痫样起始的优势。这些发现表明，腹侧 mEC 比背侧 mEC 更有可能引发过度兴奋放电，而癫痫发作的传播高度依赖于 mEC 中的 GABA 能表达水平。
