Brain-derived Neurotrophic Factor Transgenic Mice Exhibit Passive Avoidance Deficits, Increased Seizure Severity and in Vitro Hyperexcitability in the Hippocampus and Entorhinal Cortex

Neuroscience. 1999;93(4):1491-506. doi: 10.1016/s0306-4522(99)00296-1.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Animals
  • Avoidance Learning / physiology*
  • Behavior, Animal / physiology
  • Blotting, Northern
  • Brain Chemistry / genetics
  • Brain-Derived Neurotrophic Factor / genetics*
  • Dentate Gyrus / physiopathology*
  • Electrophysiology
  • Entorhinal Cortex / physiopathology*
  • Epilepsy / chemically induced
  • Epilepsy / physiopathology*
  • Excitatory Amino Acid Agonists
  • Gene Expression / physiology
  • Hot Temperature
  • In Situ Hybridization
  • Kainic Acid
  • Long-Term Potentiation / physiology
  • Maze Learning / physiology
  • Memory / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Neuronal Plasticity / physiology
  • Organ Culture Techniques
  • Pain Threshold
  • RNA, Messenger / analysis
  • Swimming
  • Transgenes

Substances

  • Brain-Derived Neurotrophic Factor
  • Excitatory Amino Acid Agonists
  • RNA, Messenger
  • Kainic Acid