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 b eta-actin promoter were tested for behavioral, gross anatomical and physiol ogical abnormalities. Brain-derived neurotrophic factor messenger RNA overe xpression was widespread throughout brain. Overexpression declined with age , such that levels of overexpression decreased sharply by nine months. Brai n-derived neurotrophic factor transgenic mice had no gross deformities or b ehavioral abnormalities. However, they showed a significant passive avoidan ce deficit. This deficit was dependent on continued overexpression, and res olved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed i ncreased seizure severity in response to kainic acid. Hippocampal slices fr om brain-derived neurotrophic factor transgenic mice showed hyperexcitabili ty in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, ar ea CA1 long-term potentiation was disrupted, indicating abnormal plasticity . Our data suggest that overexpression of brain-derived neurotrophic factor i n the brain can interfere with normal brain function by causing learning im pairments and increased excitability. The results also support the hypothes is that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system. (C) 1999 IBRO. Published by Elsevier Science Ltd.