Abstract
Mice with inactivation of the Tuberous sclerosis complex-1 (Tsc1) gene in glia (Tsc1 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 Tsc1 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 Tsc1 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 Tsc1 GFAP CKO mice and was reversed by low concentrations of NMDA antagonist, indicating that excessive synaptic glutamate directly inhibited LTP. Finally, Tsc1 GFAP CKO mice exhibited deficits in two hippocampal-dependent learning paradigms. These results suggest that abnormal glutamate homeostasis predisposes to excitotoxic cell death, impaired synaptic plasticity and learning deficits in Tsc1 GFAP CKO mice.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Astrocytes / metabolism
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Brain / metabolism*
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Brain / physiopathology
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Disease Models, Animal
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Excitatory Amino Acid Antagonists / pharmacology
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Glial Fibrillary Acidic Protein / metabolism
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Glutamic Acid / metabolism*
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Hippocampus / metabolism
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Hippocampus / physiopathology
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Homeostasis / genetics
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Learning Disabilities / genetics
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Learning Disabilities / metabolism*
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Learning Disabilities / physiopathology
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Long-Term Potentiation / drug effects
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Long-Term Potentiation / genetics
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Mice
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Mice, Knockout
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Neocortex / metabolism
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Neocortex / physiopathology
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Nerve Degeneration / genetics
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Nerve Degeneration / metabolism
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Nerve Degeneration / physiopathology
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Neuronal Plasticity / genetics*
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Organ Culture Techniques
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Synaptic Transmission / genetics*
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Tuberous Sclerosis / genetics
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Tuberous Sclerosis / metabolism*
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Tuberous Sclerosis / physiopathology
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Tuberous Sclerosis Complex 1 Protein
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Tumor Suppressor Proteins / genetics
Substances
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Excitatory Amino Acid Antagonists
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Glial Fibrillary Acidic Protein
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Tsc1 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tumor Suppressor Proteins
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Glutamic Acid