SIRT1 is essential for normal cognitive function and synaptic plasticity.
Conservation of normal cognitive functions relies on the proper performance of the nervous system at the cellular and molecular level. The mammalian nicotinamide-adenine dinucleotide-dependent deacetylase SIRT1 impacts different processes potentially involved in the maintenance of brain integrity, such as chromatin remodeling, DNA repair, cell survival, and neurogenesis. Here we show that SIRT1 is expressed in neurons of the hippocampus, a key structure in learning and memory. Using a combination of behavioral and electrophysiological paradigms, we analyzed the effects of SIRT1 deficiency and overexpression on mouse learning and memory as well as on synaptic plasticity. We demonstrated that the absence of SIRT1 impaired cognitive abilities, including immediate memory, classical conditioning, and spatial learning. In addition, we found that the cognitive deficits in SIRT1 knock-out (KO) mice were associated with defects in synaptic plasticity without alterations in basal synaptic transmission or NMDA receptor function. Brains of SIRT1-KO mice exhibited normal morphology and dendritic spine structure but displayed a decrease in dendritic branching, branch length, and complexity of neuronal dendritic arbors. Also, a decrease in extracellular signal-regulated kinase 1/2 phosphorylation and altered expression of hippocampal genes involved in synaptic function, lipid metabolism, and myelination were detected in SIRT1-KO mice. In contrast, mice with high levels of SIRT1 expression in brain exhibited regular synaptic plasticity and memory. We conclude that SIRT1 is indispensable for normal learning, memory, and synaptic plasticity in mice.
Michán
Shaday
S
Paul F. Glenn Laboratories, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Li
Ying
Y
Chou
Maggie Meng-Hsiu
MM
Parrella
Edoardo
E
Ge
Huanying
H
Long
Jeffrey M
JM
Allard
Joanne S
JS
Lewis
Kaitlyn
K
Miller
Marshall
M
Xu
Wei
W
Mervis
Ronald F
RF
Chen
Jing
J
Guerin
Karen I
KI
Smith
Lois E H
LE
McBurney
Michael W
MW
Sinclair
David A
DA
Baudry
Michel
M
de Cabo
Rafael
R
Longo
Valter D
VD
D000818:Animals; D003071:Cognition / Q000502:physiology*; D049229:Dendritic Spines / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000235:genetics*; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D056564:Sirtuin 1 / Q000032:analysis / Q000235:genetics*; D014018:Tissue Distribution
C470545:Sirt1 protein, mouse; D056564:Sirtuin 1