Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
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
Substances
-
Excitatory Amino Acid Agonists
-
Excitatory Amino Acid Antagonists
-
Muscarinic Agonists
-
Receptors, N-Methyl-D-Aspartate
-
Pilocarpine
-
Serine
-
Scopolamine
-
D-Amino-Acid Oxidase
-
Racemases and Epimerases
-
serine racemase