The aPKC-CBP Pathway Regulates Adult Hippocampal Neurogenesis in an Age-Dependent Manner.
While epigenetic modifications have emerged as attractive substrates to integrate environmental changes into the determination of cell identity and function, specific signals that directly activate these epigenetic modifications remain unknown. Here, we examine the role of atypical protein kinase C (aPKC)-mediated Ser436 phosphorylation of CBP, a histone acetyltransferase, in adult hippocampal neurogenesis and memory. Using a knockin mouse strain (CbpS436A) in which the aPKC-CBP pathway is deficient, we observe impaired hippocampal neuronal differentiation, maturation, and memory and diminished binding of CBP to CREB in 6-month-old CbpS436A mice, but not at 3 months of age. Importantly, elevation of CREB activity rescues these deficits, and CREB activity is reduced whereas aPKC activity is increased in the murine hippocampus as they age from 3 to 6 months regardless of genotype. Thus, the aPKC-CBP pathway is a homeostatic compensatory mechanism that modulates hippocampal neurogenesis and memory in an age-dependent manner in response to reduced CREB activity.
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Ayden
A
Gouveia
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
Karolynn
K
Hsu
Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Yosuke
Y
Niibori
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
Matthew
M
Seegobin
Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Gonzalo I
GI
Cancino
Division of Metabolism, Department of Pediatrics, Johns Hopkins Medical School, Baltimore, MD 21287, USA.
Ling
L
He
Department of Medicine and Pediatrics, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
Fredric E
FE
Wondisford
Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Steffany
S
Bennett
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Diane
D
Lagace
Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Psychology, University of Toronto, Toronto, ON M5G 1X5, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1X5, Canada.
Paul W
PW
Frankland
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8M5, Canada. Electronic address: jiwang@ohri.ca.
Jing
J
Wang
D000367:Age Factors; D000818:Animals; D015415:Biomarkers; D050882:CREB-Binding Protein / Q000378:metabolism*; D002454:Cell Differentiation; D006624:Hippocampus / Q000378:metabolism*; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction
D015415:Biomarkers; D050882:CREB-Binding Protein; C115015:PKC-3 protein; D011493:Protein Kinase C