Yim Man Yi, Hanuschkin Alexander, Wolfart Jakob
Department of Mathematics, University of Hong Kong, Hong Kong.
Hippocampus. 2015 Mar;25(3):297-308. doi: 10.1002/hipo.22373. Epub 2014 Nov 4.
The dentate gyrus (DG) is thought to enable efficient hippocampal memory acquisition via pattern separation. With patterns defined as spatiotemporally distributed action potential sequences, the principal DG output neurons (granule cells, GCs), presumably sparsen and separate similar input patterns from the perforant path (PP). In electrophysiological experiments, we have demonstrated that during temporal lobe epilepsy (TLE), GCs downscale their excitability by transcriptional upregulation of "leak" channels. Here we studied whether this cell type-specific intrinsic plasticity is in a position to homeostatically adjust DG network function. We modified an established conductance-based computer model of the DG network such that it realizes a spatiotemporal pattern separation task, and quantified its performance with and without the experimentally constrained leaky GC phenotype. Two proposed TLE seizure mechanisms were implemented in various degrees and combinations: recurrent GC excitation via mossy fiber sprouting and increased PP input. While increasing PP strength degraded pattern separation only gradually, already the slight elevation of sprouting drastically (non-linearly) impaired pattern separation. In most tested hyperexcitable networks, leaky GCs ameliorated pattern separation. However, in some sprouting situations with all-or-none seizure behavior, pattern separation was disabled with and without leaky GCs. In the mild sprouting (and PP increase) region of non-linear impairment, leaky GCs were particularly effective in restoring pattern separation performance. These results are compatible with the hypothesis that the experimentally observed intrinsic rescaling of GCs serves to maintain the physiological function of the DG network.
齿状回(DG)被认为可通过模式分离实现高效的海马体记忆获取。模式被定义为时空分布的动作电位序列,主要的DG输出神经元(颗粒细胞,GCs)大概会稀疏并分离来自穿通通路(PP)的相似输入模式。在电生理实验中,我们已经证明,在颞叶癫痫(TLE)期间,GCs通过“泄漏”通道的转录上调来降低其兴奋性。在这里,我们研究了这种细胞类型特异性的内在可塑性是否能够稳态调节DG网络功能。我们修改了一个已建立的基于电导的DG网络计算机模型,使其实现时空模式分离任务,并在有和没有实验约束的漏电GC表型的情况下量化其性能。两种提出的TLE癫痫发作机制以不同程度和组合实施:通过苔藓纤维发芽的GCs反复兴奋和增加PP输入。虽然增加PP强度只会逐渐降低模式分离,但已经轻微升高的发芽会急剧(非线性)损害模式分离。在大多数测试的过度兴奋网络中,漏电的GCs改善了模式分离。然而,在一些具有全或无癫痫发作行为的发芽情况下,无论有无漏电的GCs,模式分离都会被禁用。在非线性损伤的轻度发芽(和PP增加)区域,漏电的GCs在恢复模式分离性能方面特别有效。这些结果与以下假设一致,即实验观察到的GCs内在重新缩放有助于维持DG网络的生理功能。
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