Somatic gene transfer of cAMP response element-binding protein attenuates memory impairment in aging rats.
cAMP response element-binding protein (CREB) is important for the formation and facilitation of long-term memory in diverse models. However, to our knowledge, involvement of CREB in age-associated memory impairment has not been reported. Here, we use a recombinant adeno-associated virus vector to obtain stable transgenic expression of CREB as well as the inducible cAMP early repressor (ICER) in the hippocampus of adult rats. In a longitudinal study, we show that somatic gene transfer of both CREB and ICER does not alter long-term memory in young (3-month-old) rats. However, at 15 months of age, the same CREB-transduced rats show significantly better long-term memory in spatial-navigation and passive-avoidance tasks compared with their equally aged control littermates, and a threshold effect is evident. In contrast, the aged ICER-transduced rats demonstrate significantly reduced memory in comparison with the same control group. Hippocampal CREB gene transfer prevented the aging-related decrease in long-term memory found in the control rats. These data suggest that elevation of CREB protein levels in a subset of hippocampal neurons as achieved by somatic cell gene transfer might compensate for general deficits in molecular mechanisms underlying age-related memory loss in rats and, therefore, attenuate long-term-memory impairment during normal aging.
Mouravlev
Alexandre
A
Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Dunning
Jane
J
Young
Deborah
D
During
Matthew J
MJ
D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000235:genetics*; D015316:Genetic Therapy; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000628:therapy*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014161:Transduction, Genetic; D019076:Transgenes
D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger