Persistent increase of D-aspartate in D-aspartate oxidase mutant mice induces a precocious hippocampal age-dependent synaptic plasticity and spatial memory decay.
The atypical amino acid d-aspartate (d-Asp) occurs at considerable amounts in the developing brain of mammals. However, during postnatal life, d-Asp levels diminish following the expression of d-aspartate oxidase (DDO) enzyme. The strict control of DDO over its substrate d-Asp is particularly evident in the hippocampus, a brain region crucially involved in memory, and highly vulnerable to age-related deterioration processes. Herein, we explored the influence of deregulated higher d-Asp brain content on hippocampus-related functions during aging of mice lacking DDO (Ddo(-/-)). Strikingly, we demonstrated that the enhancement of hippocampal synaptic plasticity and cognition in 4/5-month-old Ddo(-/-) mice is followed by an accelerated decay of basal glutamatergic transmission, NMDAR-dependent LTP and hippocampus-related reference memory at 13/14 months of age. Therefore, the precocious deterioration of hippocampal functions observed in mutants highlights for the first time a role for DDO enzyme in controlling the rate of brain aging process in mammals.
Errico
Francesco
F
CEINGE Biotecnologie Avanzate, Via Comunale Margherita 482- 80145, Naples, Italy.
Nisticò
Robert
R
Napolitano
Francesco
F
Oliva
Alessandra Bonito
AB
Romano
Rosaria
R
Barbieri
Federica
F
Florio
Tullio
T
Russo
Claudio
C
Mercuri
Nicola B
NB
Usiello
Alessandro
A
D000367:Age Factors; D000818:Animals; D003213:Conditioning, Psychological / Q000502:physiology; D050804:D-Aspartate Oxidase / Q000235:genetics / Q000378:metabolism*; D026603:D-Aspartic Acid / Q000378:metabolism*; D005239:Fear / Q000502:physiology; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
D026603:D-Aspartic Acid; D050804:D-Aspartate Oxidase