Impaired D-serine-mediated cotransmission mediates cognitive dysfunction in epilepsy

• Published in: The Journal of neuroscience Vol. 33; no. 32; pp. 13066 - 13080
• Main Authors: Klatte, Katharina, Kirschstein, Timo, Otte, David, Pothmann, Leonie, Müller, Lorenz, Tokay, Tursonjan, Kober, Maria, Uebachs, Mischa, Zimmer, Andreas, Beck, Heinz
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 07.08.2013
• Subjects: Allosteric Regulation - drug effects; Animals; Binding Sites - drug effects; Cognition Disorders - drug therapy; Cognition Disorders - etiology; Cognition Disorders - pathology; D-Amino-Acid Oxidase - genetics; D-Amino-Acid Oxidase - metabolism; Disease Models, Animal; Epilepsy, Temporal Lobe - chemically induced; Epilepsy, Temporal Lobe - complications; Epilepsy, Temporal Lobe - diet therapy; Epilepsy, Temporal Lobe - pathology; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Agonists - therapeutic use; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; Gene Expression Regulation - drug effects; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; In Vitro Techniques; Male; Maze Learning - drug effects; Muscarinic Agonists - toxicity; Pilocarpine - toxicity; Protein Binding - drug effects; Racemases and Epimerases - genetics; Racemases and Epimerases - metabolism; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - metabolism; Scopolamine - toxicity; Serine - pharmacology; Serine - therapeutic use; Synapses - drug effects; Synapses - metabolism; Synaptic Transmission - drug effects; Synaptic Transmission - physiology
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.5423-12.2013

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.