Impaired D-serine-mediated cotransmission mediates cognitive dysfunction in epilepsy
The modulation of synaptic plasticity by NMDA receptor (NMDAR)-mediated processes is essential for many forms of learning and memory. Activation of NMDARs by glutamate requires the binding of a coagonist to a regulatory site of the receptor. In many forebrain regions, this coagonist is d-serine. Her...
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Published in | The Journal of neuroscience Vol. 33; no. 32; pp. 13066 - 13080 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Society for Neuroscience
07.08.2013
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Subjects | |
Online Access | Get full text |
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Summary: | The modulation of synaptic plasticity by NMDA receptor (NMDAR)-mediated processes is essential for many forms of learning and memory. Activation of NMDARs by glutamate requires the binding of a coagonist to a regulatory site of the receptor. In many forebrain regions, this coagonist is d-serine. Here, we show that experimental epilepsy in rats is associated with a reduction in the CNS levels of d-serine, which leads to a desaturation of the coagonist binding site of synaptic and extrasynaptic NMDARs. In addition, the subunit composition of synaptic NMDARs changes in chronic epilepsy. The desaturation of NMDARs causes a deficit in hippocampal long-term potentiation, which can be rescued with exogenously supplied d-serine. Importantly, exogenous d-serine improves spatial learning in epileptic animals. These results strongly suggest that d-serine deficiency is important in the amnestic symptoms of temporal lobe epilepsy. Our results point to a possible clinical utility of d-serine to alleviate these disease manifestations. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 K.K. and T.K. contributed equally to this work. Author contributions: K.K., T.K., M.U., A.Z., and H.B. designed research; K.K., T.K., D.O., L.P., L.M., T.T., and M.K. performed research; K.K., D.O., L.P., T.T., and M.K. analyzed data; K.K. and H.B. wrote the paper. |
ISSN: | 0270-6474 1529-2401 1529-2401 |
DOI: | 10.1523/jneurosci.5423-12.2013 |