Tonini R, Franceschetti S, Parolaro D, Sala M, Mancinelli E, Tininini S, Brusetti R, Sancini G, Brambilla R, Martegani E, Sturani E, Zippel R
Dipartimento di Fisiologia e Biochimica Generali, Università degli Studi di Milano, 20133 Milan, Italy.
Mol Cell Neurosci. 2001 Dec;18(6):691-701. doi: 10.1006/mcne.2001.1050.
Ras-GRF1 is a neuron-specific guanine nucleotide exchange factor for Ras proteins. Mice lacking Ras-GRF1 (-/-) are severely impaired in amygdala-dependent long-term synaptic plasticity and show higher basal synaptic activity at both amygdala and hippocampal synapses (Brambilla et al., 1997). In the present study we investigated the effects of Ras-GRF1 deletion on hippocampal neuronal excitability. Electrophysiological analysis of both primary cultured neurons and adult hippocampal slices indicated that Ras-GRF1-/- mice displayed neuronal hyperexcitability. Ras-GRF1-/- hippocampal neurons showed increased spontaneous activity and depolarized resting membrane potential, together with a higher firing rate in response to injected current. Changes in the intrinsic excitability of Ras-GRF1-/- neurons can entail these phenomena, suggesting that Ras-GRF1 deficiency might alter the balance between ionic conductances. In addition, we showed that mice lacking Ras-GRF1 displayed a higher seizure susceptibility following acute administration of convulsant drugs. Taken together, these results demonstrated a role for Ras-GRF1 in neuronal excitability.
Ras-GRF1是一种针对Ras蛋白的神经元特异性鸟嘌呤核苷酸交换因子。缺乏Ras-GRF1的小鼠（-/-）在杏仁核依赖性长期突触可塑性方面严重受损，并且在杏仁核和海马突触处均表现出较高的基础突触活性（Brambilla等人，1997年）。在本研究中，我们研究了Ras-GRF1缺失对海马神经元兴奋性的影响。对原代培养神经元和成年海马切片的电生理分析表明，Ras-GRF1-/-小鼠表现出神经元兴奋性过高。Ras-GRF1-/-海马神经元表现出自发性活动增加和静息膜电位去极化，同时对注入电流的放电频率更高。Ras-GRF1-/-神经元内在兴奋性的变化可能导致这些现象，这表明Ras-GRF1缺乏可能会改变离子电导之间的平衡。此外，我们表明，缺乏Ras-GRF1的小鼠在急性给予惊厥药物后表现出更高的癫痫易感性。综上所述，这些结果证明了Ras-GRF1在神经元兴奋性中的作用。
