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Exzitotoxizität im ZNS bei Mausmutanten mit veränderten Glutamatrezeptoren

Coserea, Irinel Andreea

English Title: Excitotoxicity in mice with genetic modified glutamate receptors

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Abstract

Excitotoxicity is a detrimental condition that accompanies acute brain damage such as stroke. Extensive studies have documented that excitotoxicity is mediated by the NMDA receptors and the excessive Ca2+ influx triggered by prolonged NMDA channel activation. However, the contribution to excitotoxicity by the two main NMDA receptor subtypes in principal neurons, NR2A and NR2B has remained enigmatic. This issue was investigated in cultured cortical neurons prepared from wild-type and gene-targeted mice expressing NR2A or NR2B with altered signalling characteristics. Excitotoxicity experiments including subtype-specific pharmacological tools and electrophysiological measurements were performed. Cultured neurons recapitulate the developmental expression profile of the two main NMDA receptor subunits NR2A and NR2B: at 14DIV neurons express NR2B and very low levels of NR2A. At 21DIV, NR2A subunit expression becomes as prominent as the NR2B subunit. In cultured neurons expressing NR2A only in its C-terminally truncated form, NMDA-mediated excitotoxicity occurred efficiently via the NR2B channels, both at 14 and 21DIV. This probably reflects the inability of truncated NR2A channels to access the “death programme“. Moreover, NMDA-triggered Ca2+-influx at 21DIV was suppressed by the NR2B subunit-specific blocker ifenprodil, indicating that Ca2+-influx occurred only through NR2B channels. Thus, in the absence of fully functional NR2A channels, excitotoxicity can be triggered only by the NR2B subtype. In cultured neurons expressing NR2B only in its C-terminally truncated form, exposure to NMDA had no toxic effect and no Ca2+-influx could be measured. Extensive electrophysiological experiments indicated a strong reduction of synaptic NMDA channels, suggesting that normal NR2B signalling is required for the postsynaptic presence of the NR2A channels. Whereas in young (14DIV) wild-type cultures NMDA-mediated toxicity was mediated solely by the NR2B channels, due to the lack of NR2A expression at this young stage, in older cultures (21DIV) both subtypes were found to be responsible for excitotoxicity. Notably, blocking any of the two subtypes did not reduce toxicity, due to the ability of the other subtype to compensate with no apparent time delay. In summary, this study indicates that both NR2A and NR2B subunits are playing a critical role in excitotoxicity, and any NMDA receptor subtype specific therapeutic intervention in stroke would lead to a failure.

Item Type: Dissertation
Supervisor: Prof. Dr. Monyer, Hannah
Date of thesis defense: 3 March 2005
Date Deposited: 06 Apr 2005 12:30
Date: 2005
Faculties / Institutes: Medizinische Fakultät Heidelberg > Neurologische Universitätsklinik
Subjects: 570 Life sciences
Controlled Keywords: Exzitotoxizität, Glutamatrezeptoren, Mausmutanten
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