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. 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.
Laboratory of Experimental Epileptology, Department of Epileptology and Institute of Molecular Psychiatry, University of Bonn, D-53127 Bonn, Germany.
Katharina
K
Klatte
Timo
T
Kirschstein
David
D
Otte
Leonie
L
Pothmann
Lorenz
L
Müller
Tursonjan
T
Tokay
Maria
M
Kober
Mischa
M
Uebachs
Andreas
A
Zimmer
Heinz
H
Beck
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D003605:D-Amino-Acid Oxidase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000150:complications / Q000178:diet therapy / Q000473:pathology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018721:Muscarinic Agonists / Q000633:toxicity; D010862:Pilocarpine / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects; D019998:Racemases and Epimerases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012601:Scopolamine / Q000633:toxicity; D012694:Serine / Q000494:pharmacology / Q000627:therapeutic use*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D000099300:Serine Racemase
D003605:D-Amino-Acid Oxidase; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018721:Muscarinic Agonists; D010862:Pilocarpine; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012601:Scopolamine; D012694:Serine; D000099300:Serine Racemase