Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex

NEUROBIOLOGY OF DISEASE

卷:28

Article

Zeng, Ling-Hui ; Ouyang, Yannan ; Gazit, Vered ; Cirrito, John R. ; Jansen, Laura A. ; Ess, Kevin C. ; Yamada, Kelvin A. ; Wozniak, David F. ; Holtzman, David M. ; Gutmann, David H. ; Wong, Michael

关键词: Glia;    astrocyte;    glutamate transporter;    microdialysis;    long-term;    potentiation;    learning;    excitotoxicity;    seizure;    epilepsy;   

DOI  :  10.1016/j.nbd.2007.07.015

来源: Elsevier

【 摘 要 】

Mice with inactivation of the Tuberous sclerosis complex-1 (Tscl) gene in glia (Tscl(GFAP)CKO mice) have deficient astrocyte glutamate transporters and develop seizures, suggesting that abnormal glutamate homeostasis contributes to neurological abnormalities in these mice. We examined the hypothesis that Tscl(GFAP)CKO mice have elevated extracellular brain glutamate levels that may cause neuronal death, abnormal glutamatergic synaptic function, and associated impairments in behavioral learning. In vivo microdialysis documented elevated glutamate levels in hippocampi of Tscl(GFAP)CKO mice and several cell death assays demonstrated neuronal death in hippocampus and neocortex. Impairment of long-term potentiation (LTP) with tetanic stimulation was observed in hippocampal slices from Tscl(GFAP)CKO mice and was reversed by low concentrations of NMDA antagonist, indicating that excessive synaptic glutamate directly inhibited LTP. Finally, Tscl(GFAP)CKO mice exhibited deficits in two hippocampal-dependent learning paradigms. These results suggest that abnormal glutamate homeostasis predisposes to excitutoxic cell death, impaired synaptic plasticity and learning deficits in Tscl(GFAP)CKO mice. (c) 2007 Elsevier Inc. All rights reserved.

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