Astrocytic Glutamate Release-Induced Transient Depolarization and Epileptiform Discharges in Hippocampal CA1 Pyramidal Neurons
Tóm tắt
A paroxysmal depolarization shift (PDS) has been suggested to be a hallmark for epileptic activity in partial-onset seizures. By monitoring membrane potentials and currents in pairs of pyramidal neurons and astrocytes with dual patch-clamp recording and exocytosis of vesicles from astrocytes with two-photon laser scanning microscopy in hippocampal slices, we found that infusion of inositol 1,4,5-trisphosphate (IP3) into astrocytes by patch pipettes induced astrocytic glutamate release that triggered a transient depolarization (TD) and epileptiform discharges in CA1 pyramidal neurons. The TD is due to a tetrodotoxin (TTX)-insensitive slowly decaying transient inward current (STC). Astrocytic glutamate release simultaneously triggers both the STC in pyramidal neurons and a transport current (TC) in astrocytes. The neuronal STC is mediated by ionotropic glutamate receptors leading to the TD and epileptiform discharges; while the astrocytic TC is a glutamate reuptake current resulting from transporting released glutamate into the patched astrocyte. Fusion of a large vesicle in astrocytes was immediately followed by an astrocytic TC, suggesting that the fused vesicle contains glutamate. Both fusion of large vesicles and astrocytic TCs were blocked by tetanus toxin (TeNT), suggesting that astrocytic glutamate release is via SNARE-dependent exocytosis of glutamate-containing vesicles. In the presence of TTX, the epileptogenic reagent, 4-AP, also induced similar neuronal STCs and astrocytic TCs, suggesting that astrocytic glutamate release may play an epileptogenic role in initiation of epileptic seizures under pathological conditions. Our study provides a novel mechanism, astrocytic release of glutamate, for seizure initiation.
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Tài liệu tham khảo
Bernard C, Hirsch J, and Ben-Ari Y. [Glutamatergic excitatory receptors and temporal lobe epilepsy]. Rev Neurol (Paris) 153 Suppl 1: S14-24, 1997.
Fiacco TA and McCarthy KD. Intracellular astrocyte calcium waves in situ increase the frequency of spontaneous AMPA receptor currents in CA1 pyramidal neurons. J Neurosci 24(3): 722–32, 2004.
Hertz L, Murthy CRK, and Schousboe A. Metabolism of glutamate and related amino acids. In: The Biochemical Pathology of Astrocytes (Norenberg, M. D. Hertz, L. and Schousboe, A, eds), pp. 395–406. Alan R. Liss, New York, 1988.
Johnston D and Brown TH. Control theory applied to neural networks illuminates synaptic basis of interictal epileptiform activity. Adv Neurol 44: 263–274, 1986.
Prince DA and Connors BW. Mechanisms of interictal epileptogenesis. Adv Neurol 44: 275–299, 1986.
Prince DA, Salin P, Tseng GF, Hoffman S, and Parada I. Axonal sprouting and epileptogenesis. Adv Neurol 72: 1–8, 1997.
Ye ZC, Ransom BR, and Sontheimer H. (1R, 3S)-1-aminocyclopentane-1,3-dicarboxylic acid (RS-ACPD) reduces intracellular glutamate levels in astrocytes. J Neurochem 79: 756–766, 2001.