| Animal Research: |
| Neuropsychopharmacology, 2008, 33(5):1004-1018. | | D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning.[Pubmed: 17625504] | The contributions of hippocampal long-term depression (LTD) to explicit learning and memory are poorly understood. Electrophysiological and behavioral studies examined the effects of modulating NMDA receptor-dependent LTD on spatial learning in the Morris water maze (MWM).
METHODS AND RESULTS:
The NMDA receptor co-agonist D-Serine substantially enhanced NR2B-dependent LTD, but not long-term potentiation (LTP) or depotentiation, in hippocampal slices from adult wild type mice. Exogenous D-Serine did not alter MWM acquisition, but substantially enhanced subsequent reversal learning of a novel target location and performance in a delayed-matching-to-place task. Conversely, an NR2B antagonist disrupted reversal learning and promoted perseveration. Endogenous synaptic D-Serine likely saturates during LTP induction because exogenous D-Serine rescued deficient LTP and MWM acquisition in Grin1(D481N) mutant mice having a lower D-Serine affinity.
CONCLUSIONS:
Thus, D-Serine may enhance a form of hippocampal NR2B-dependent LTD that contributes to spatial reversal learning. By enhancing this form of synaptic plasticity, D-Serine could improve cognitive flexibility in psychiatric disorders characterized by perseveration of aberrant ideation or behaviors. | | Neurosci Lett,2005 Apr 29;379(1):7-12. | | D-serine enhances impaired long-term potentiation in CA1 subfield of hippocampal slices from aged senescence-accelerated mouse prone/8.[Pubmed: 15814189] | The molecular and cellular mechanisms underlying the cognitive deficiency of senescence-accelerated mouse prone/8 (SAMP8) have been attributed to many pathological changes in neurons. Recently, increasing evidence has shown that astrocytes, by mean of D-Serine, involve in the process of synaptic transmission.
METHODS AND RESULTS:
Here we reported that the long-term potentiation (LTP) in CA1 area of hippocampal slices prepared from 2-, 6- and 12-month-old SAMP8 significantly decreased with age. Meanwhile, the LTP in the slices of 6- and 12-month-old mice markedly decreased below that of the age-matched normal strain SAMR1. Supplement with exogenous D-Serine, a main product of astrocytes and a coagonist at the "glycin-binding" site of N-methyl-d-aspartate (NMDA) receptors, not only directly enhanced the deficient LTP but also rescued the abolished LTP by d-amino acid oxidase (DAAO) in slices from 12-month-old SAMP8. This ameliorative effect of D-Serine was inhibited by either AP-V or 5,7-dichlorokynurenic acid (DCKA).
CONCLUSIONS:
These results suggest that absence of D-Serine or dysfunction of the astrocytes possibly was one of mechanisms underlying the decrease of NMDA receptor-dependent LTP and cognition in aged SAMP8. |
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