Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex
| Autor: | Kevin C. Ess, David F. Wozniak, Ling-Hui Zeng, Vered Gazit, John R. Cirrito, Kelvin A. Yamada, Laura A. Jansen, David M. Holtzman, Michael Wong, Yannan Ouyang, David H. Gutmann |
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| Rok vydání: | 2007 |
| Předmět: |
Microdialysis
Long-Term Potentiation Excitotoxicity Glutamic Acid Neocortex Biology medicine.disease_cause Hippocampus Synaptic Transmission Article Tuberous Sclerosis Complex 1 Protein lcsh:RC321-571 Mice Glutamatergic Organ Culture Techniques Glutamate homeostasis Tuberous Sclerosis Glia Glial Fibrillary Acidic Protein medicine Learning Animals Homeostasis lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Mice Knockout Neuronal Plasticity Learning Disabilities Tumor Suppressor Proteins Glutamate receptor Brain Long-term potentiation Disease Models Animal medicine.anatomical_structure nervous system Neurology Astrocytes Nerve Degeneration Synaptic plasticity NMDA receptor Glutamate transporter Astrocyte Excitatory Amino Acid Antagonists Neuroscience |
| Zdroj: | Neurobiology of Disease, Vol 28, Iss 2, Pp 184-196 (2007) |
| ISSN: | 0969-9961 |
| DOI: | 10.1016/j.nbd.2007.07.015 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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