The Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; The Cain Foundation Laboratories, The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund Street, Suite 1225, Houston, TX, 77030, USA.
Eur J Neurosci. 2013 Oct;38(8):3115-27. doi: 10.1111/ejn.12315. Epub 2013 Jul 24.
Neuronal networks are thought to gradually adapt to altered neuronal activity over many hours and days. For instance, when activity is increased by suppressing synaptic inhibition, excitatory synaptic transmission is reduced. The underlying compensatory cellular and molecular mechanisms are thought to contribute in important ways to maintaining normal network operations. Seizures, due to their massive and highly synchronised discharging, probably challenge the adaptive properties of neurons, especially when seizures are frequent and intense - a condition common in early childhood. In the experiments reported here, we used rat and mice hippocampal slice cultures to explore the effects that recurring seizure-like activity has on the developing hippocampus. We found that developing networks adapted rapidly to recurring synchronised activity in that the duration of seizure-like events was reduced by 42% after 4 h of activity. At the same time, the frequency of spontaneous excitatory postsynaptic currents in pyramidal cells, the expression of biochemical biomarkers for glutamatergic synapses and the branching of pyramidal cell dendrites were all dramatically reduced. Experiments also showed that the reduction in N-methyl-D-aspartate receptor subunits and postsynaptic density protein 95 expression were N-methyl-D-aspartate receptor-dependent. To explore calcium signaling mechanisms in network adaptation, we tested inhibitors of calcineurin, a protein phosphatase known to play roles in synaptic plasticity and activity-dependent dendrite remodeling. We found that FK506 was able to prevent all of the electrophysiological, biochemical, and anatomical changes produced by synchronised network activity. Our results show that hippocampal pyramidal cells and their networks adapt rapidly to intense synchronised activity and that calcineurin play an important role in the underlying processes.
神经元网络被认为能够在数小时和数天的时间里逐渐适应改变的神经元活动。例如，当通过抑制突触抑制来增加活动时，兴奋性突触传递会减少。人们认为，潜在的补偿性细胞和分子机制在维持正常网络运作方面发挥了重要作用。癫痫发作由于其大规模和高度同步放电，可能对神经元的适应能力构成挑战，尤其是在癫痫发作频繁且强烈的情况下——这种情况在儿童早期很常见。在本报告的实验中，我们使用大鼠和小鼠海马切片培养物来探索反复癫痫样活动对发育中的海马体的影响。我们发现，发育中的网络能够快速适应反复同步活动，即在 4 小时的活动后，癫痫样事件的持续时间减少了 42%。与此同时，锥体神经元中自发性兴奋性突触后电流的频率、谷氨酸能突触的生化生物标志物的表达以及锥体神经元树突的分支都显著减少。实验还表明，N-甲基-D-天冬氨酸受体亚基和突触后密度蛋白 95 表达的减少依赖于 N-甲基-D-天冬氨酸受体。为了探索网络适应中的钙信号转导机制，我们测试了钙调神经磷酸酶的抑制剂，钙调神经磷酸酶是一种已知在突触可塑性和活动依赖性树突重塑中发挥作用的蛋白磷酸酶。我们发现 FK506 能够防止同步网络活动产生的所有电生理、生化和解剖变化。我们的研究结果表明，海马锥体神经元及其网络能够快速适应强烈的同步活动，钙调神经磷酸酶在潜在的过程中发挥着重要作用。
