Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.
Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.
Croll
S D
SD
Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
Suri
C
C
Compton
D L
DL
Simmons
M V
MV
Yancopoulos
G D
GD
Lindsay
R M
RM
Wiegand
S J
SJ
Rudge
J S
JS
Scharfman
H E
HE
D000367:Age Factors; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D001522:Behavior, Animal / Q000502:physiology; D015152:Blotting, Northern; D001923:Brain Chemistry / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D018891:Dentate Gyrus / Q000503:physiopathology*; D004594:Electrophysiology; D018728:Entorhinal Cortex / Q000503:physiopathology*; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists; D015870:Gene Expression / Q000502:physiology; D006358:Hot Temperature; D017403:In Situ Hybridization; D007608:Kainic Acid; D017774:Long-Term Potentiation / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology; D009924:Organ Culture Techniques; D017288:Pain Threshold; D012333:RNA, Messenger / Q000032:analysis; D013550:Swimming; D019076:Transgenes
D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D012333:RNA, Messenger; D007608:Kainic Acid