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The Journal of Neuroscience, September 8, 2004, 24(36):7958-7963; doi:10.1523/JNEUROSCI.1948-04.2004

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Behavioral/Systems/Cognitive
Brain-Derived Neurotrophic Factor Plays a Critical Role in Contextual Fear Conditioning

Ingrid Y.C. Liu,¹ W. Ernest Lyons,² Laura A. Mamounas,² and Richard F. Thompson¹

¹Neuroscience Program, University of Southern California, Los Angeles, California 90089-2520, and ²Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

In this study, brain-derived neurotrophic factor (BDNF) heterozygous knock-outs were tested on fear conditioning, and their wild-type littermates were used as controls. Results showed that BDNF^+/- mice are impaired in contextual learning, whereas tone learning remains intact. Because BDNF is involved in synaptic transmission and contextual learning is hippocampal dependent, we hypothesized that this deficit is attributable to abnormal BDNF-modulated synaptic plasticity in the hippocampus. A "gain-of-function" experiment was performed next by infusing recombinant BDNF protein into the hippocampal formation to investigate whether this deficit can be rescued. Infusion of BDNF protein into the hippocampus appeared to partially restore contextual fear learning of BDNF^+/- mice. In conclusion, the present study suggests that BDNF plays a critical role in fear conditioning. Loss of one copy of the BDNF gene leads to impairment of contextual fear learning in BDNF^+/-. This deficit can be partially rescued by infusing BDNF protein into the hippocampus. Other brain regions interacting with the hippocampus in the context conditioned stimulus pathway, for example, the amygdala, may also require normal BDNF expression levels to fully rescue this impairment.

Key words: BDNF; knock-out; heterozygous; fear conditioning; context; tone

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Received May 19, 2004; revised July 21, 2004; accepted July 21, 2004.

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