Targeted gene mutation of E2F1 evokes age-dependent synaptic disruption and behavioral deficits.
Aberrant expression and activation of the cell cycle protein E2F1 in neurons has been implicated in many neurodegenerative diseases. As a transcription factor regulating G1 to S phase progression in proliferative cells, E2F1 is often up-regulated and activated in models of neuronal death. However, despite its well-studied functions in neuronal death, little is known regarding the role of E2F1 in the mature brain. In this study, we used a combined approach to study the effect of E2F1 gene disruption on mouse behavior and brain biochemistry. We identified significant age-dependent olfactory and memory-related deficits in E2f1 mutant mice. In addition, we found that E2F1 exhibits punctated staining and localizes closely to the synapse. Furthermore, we found a mirroring age-dependent loss of post-synaptic protein-95 in the hippocampus and olfactory bulb as well as a global loss of several other synaptic proteins. Coincidently, E2F1 expression is significantly elevated at the ages, in which behavioral and synaptic perturbations were observed. Finally, we show that deficits in adult neurogenesis persist late in aged E2f1 mutant mice which may partially contribute to the behavior phenotypes. Taken together, our data suggest that the disruption of E2F1 function leads to specific age-dependent behavioral deficits and synaptic perturbations. E2F1 is a transcription factor regulating cell cycle progression and apoptosis. Although E2F1 dysregulation under toxic conditions can lead to neuronal death, little is known about its physiologic activity in the healthy brain. Here, we report significant age-dependent olfactory and memory deficits in mice with dysfunctional E2F1. Coincident with these behavioral changes, we also found age-matched synaptic disruption and persisting reduction in adult neurogenesis. Our study demonstrates that E2F1 contributes to physiologic brain structure and function.
Department of Pathology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania, USA.
Jenhao H
JH
Ting
David R
DR
Marks
Stephanie S
SS
Schleidt
Joanna N
JN
Wu
Jacob W
JW
Zyskind
Kathryn A
KA
Lindl
Julie A
JA
Blendy
R Christopher
RC
Pierce
Kelly L
KL
Jordan-Sciutto
D000375:Aging / Q000235:genetics* / Q000523:psychology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D050687:E2F1 Transcription Factor / Q000235:genetics*; D018390:Gene Targeting; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008568:Memory / Q000502:physiology; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D009812:Odorants; D000857:Olfaction Disorders / Q000235:genetics / Q000523:psychology; D004856:Postural Balance / Q000235:genetics / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology; D012903:Smell / Q000235:genetics / Q000502:physiology; D013569:Synapses / Q000473:pathology*; D013574:Synaptosomes / Q000502:physiology
D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse
E2F; adult neurogenesis; cell cycle; synaptic proteins; transgenic mice