Carmignoto Giorgio, Fellin Tommaso
Istituto CNR di Neuroscienze and Dipartimento di Scienze Biomediche Sperimentali, Università di Padova, Italy.
J Physiol Paris. 2006 Mar-May;99(2-3):98-102. doi: 10.1016/j.jphysparis.2005.12.008.
Synchronization of activity of anatomically distributed groups of neurons represents a fundamental event in the processing of information in the brain. While this phenomenon is believed to result from dynamic interactions within the neuronal circuitry, how exactly populations of neurons become synchronized remains largely to be clarified. We propose that astrocytes are directly involved in the generation of neuronal synchrony in the hippocampus. By using a combination of experimental approaches in hippocampal slice preparations, including patch-clamp recordings and confocal microscopy calcium imaging, we studied the effect on CA1 pyramidal neurons of glutamate released from astrocytes upon various stimuli that trigger Ca2+ elevations in these glial cells, including Schaffer collateral stimulation. We found that astrocytic glutamate evokes synchronous, slow inward currents (SICs) and Ca2+ elevations in CA1 pyramidal neurons by acting preferentially, if not exclusively, on extrasynaptic NMDA receptors. Due to desensitization, AMPA receptors were not activated by astrocytic glutamate unless cyclothiazide was present. In the virtual absence of extracellular Mg2+, glutamate released from astrocytes was found to evoke, in paired recordings, highly synchronous SICs from two CA1 pyramidal neurons and, in Ca2+ imaging experiments, Ca2+ elevations that occurred synchronously in domains composed of 2-12 CA1 neurons. In the presence of extracellular Mg2+ (1 mM), synchronous SICs in two neurons as well as synchronous Ca2+ elevations in neuronal domains were still observed, although with a reduced frequency. Our results reveal a functional link between astrocytic glutamate and extrasynaptic NMDA receptors that contributes to the overall dynamics of neuronal synchrony. Our observations also raise a series of questions on possible roles of this astrocyte-to-neuron signaling in pathological changes in the hippocampus such as excitotoxic neuronal damage or the generation of epileptiform activity.
在大脑信息处理过程中，解剖学上分散分布的神经元群活动同步化是一个基本事件。虽然人们认为这种现象是由神经元回路内的动态相互作用导致的，但神经元群体究竟如何实现同步化在很大程度上仍有待阐明。我们提出星形胶质细胞直接参与海马体中神经元同步化的产生。通过在海马体脑片制备中结合使用多种实验方法，包括膜片钳记录和共聚焦显微镜钙成像，我们研究了在各种能触发这些神经胶质细胞内钙离子浓度升高的刺激（包括施万细胞侧支刺激）下，星形胶质细胞释放的谷氨酸对CA1锥体神经元的影响。我们发现，星形胶质细胞释放的谷氨酸通过优先（如果不是唯一）作用于突触外NMDA受体，在CA1锥体神经元中诱发同步的缓慢内向电流（SICs）和钙离子浓度升高。由于脱敏作用，除非存在环噻嗪，AMPA受体不会被星形胶质细胞释放的谷氨酸激活。在几乎没有细胞外镁离子的情况下，发现在配对记录中，星形胶质细胞释放的谷氨酸能从两个CA1锥体神经元诱发高度同步的SICs，并且在钙成像实验中，在由2 - 12个CA1神经元组成的区域中同步出现钙离子浓度升高。在存在细胞外镁离子（1 mM）的情况下，仍然观察到两个神经元中的同步SICs以及神经元区域中的同步钙离子浓度升高，尽管频率有所降低。我们的结果揭示了星形同步神经元同步化总体动态。我们的观察结果还引发了一系列关于这种星形胶质细胞到神经元信号传导在海马体病理变化（如兴奋性毒性神经元损伤或癫痫样活动的产生）中可能作用的问题。
