TY - JOUR
T1 - Impaired D-Serine-Mediated cotransmission mediates cognitive dysfunction in epilepsy
AU - Klatte, Katharina
AU - Kirschstein, Timo
AU - Otte, David
AU - Pothmann, Leonie
AU - Müller, Lorenz
AU - Tokay, Tursonjan
AU - Kober, Maria
AU - Uebachs, Mischa
AU - Zimmer, Andreas
AU - Beck, Heinz
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84881169877&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84881169877&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.5423-12.2013
DO - 10.1523/jneurosci.5423-12.2013
M3 - Article
C2 - 23926260
AN - SCOPUS:84881169877
VL - 33
SP - 13066
EP - 13080
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 32
ER -