Elsevier

Neuroscience

Volume 121, Issue 2, 6 October 2003, Pages 341-354
Neuroscience

Learning deficits in forebrain-restricted brain-derived neurotrophic factor mutant mice

https://doi.org/10.1016/S0306-4522(03)00426-3Get rights and content

Abstract

Brain-derived neurotrophic factor (BDNF) participates in synaptic plasticity and the adaptive changes in the strength of communication between neurons thought to underlie aspects of behavioral adaptation. By selectively deleting BDNF from the forebrain of mice using the Cre site-specific DNA recombinase, we were able to study the requirements for BDNF in behaviors such as learning and anxiety. Early-onset forebrain-restricted BDNF mutant mice (Emx-BDNFKO) that develop in the absence of BDNF in the dorsal cortex, hippocampus, and parts of the ventral cortex and amygdala failed to learn the Morris Water Maze task, a hippocampal-dependent visuo-spatial learning task. Freezing during all phases of cued-contextual fear conditioning, a behavioral task designed to study hippocampal-dependent associative learning, was enhanced. These mice learned a brightness discrimination task well but were impaired in a more difficult pattern discrimination task. Emx-BDNFKO mice did not exhibit altered sensory processing and gating, as measured by the acoustic startle response or prepulse inhibition of the startle response. Although they were less active in an open-field arena, they did not show alterations in anxiety, as measured in the elevated-plus maze, black-white chamber or mirrored chamber tasks. Combined, these data indicate that although an absence of forebrain BDNF does not disrupt acoustic sensory processing or alter baseline anxiety, specific forms of learning are severely impaired.

Section snippets

Subjects

Early onset, forebrain-restricted BDNF mutant mice, Emx-BDNFKO mice, were generated by breeding Emx1IREScre/+ mice (Gorski et al., 2002) with BDNFneo/+ mice (Jones et al., 1994) to generate Emx1IREScre/+;BDNFneo/+ mice, which were then mated to BDNFlox/+ mice. All recombinant mice were derived from a 129/Sv embryonic stem cell line (Doetschman et al., 1985) and were backcrossed to C57BL/6J for 6–9 generations prior to behavioral testing. Of the eight potential offspring only Emx1IREScre/+; BDNF

Subjects

Emx-BDNFKO mice develop in the absence of detectable BDNF in the dorsal cortex and hippocampus, with significantly reduced expression in the ventral cortex, amygdala and septum, while retaining expression in other subcortical structures and peripheral tissues. In work described separately, no obvious anatomical abnormalities were detected in the hippocampus of Emx-BDNFKO mice at 5 weeks. Beyond 2 weeks of age, cortical volume was reduced by 20% and was accompanied by reductions in neuron soma

Emx-bdnfko mice have profound spatial learning deficits

The hidden platform water maze task is popular for testing hippocampal-dependent spatial learning ability in rodents Morris et al., 1982, Crawley et al., 1997, Crawley and Paylor, 1997, Crawley, 1999. Mice with intact hippocampal function show reductions in escape latencies and swim distances when tested over several days in this task, while those with hippocampal lesions do not (Logue et al., 1997), consistent with many other results indicating the importance of the hippocampus in spatial

Acknowledgements

This work was supported by grants MH-53668 to J.M.W., a post-doctoral traineeship MH-16880 to S.A.B. and grants from the Muscular Dystrophy Association, the American Cancer Society, the University of Colorado Council on Research and Creative Work and a Burroughs-Wellcome Fund New Investigator Award to K.R.J. We thank Julie Ernisse, Zachary Baquet, Ryan Hebert and Alison Vigers for technical support and advice.

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