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The Journal of Neuroscience, October 3, 2007, 27(40):10685-10694; doi:10.1523/JNEUROSCI.2624-07.2007

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Neurobiology of Disease
Brain-Derived Neurotrophic Factor Rescues Synaptic Plasticity in a Mouse Model of Fragile X Syndrome

Julie C. Lauterborn,¹ Christopher S. Rex,² Eniko Kramár,³ Lulu Y. Chen,¹ Vijay Pandyarajan,¹ Gary Lynch,³ and Christine M. Gall^1,2

Departments of ¹Anatomy and Neurobiology, ²Neurobiology and Behavior, and ³Psychiatry and Human Behavior, University of California, Irvine, California 92697-4292

Correspondence should be addressed to Dr. Julie C. Lauterborn, Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4292. Email: jclauter{at}uci.edu

Mice lacking expression of the fragile X mental retardation 1 (Fmr1) gene have deficits in types of learning that are dependent on the hippocampus. Here, we report that long-term potentiation (LTP) elicited by threshold levels of theta burst afferent stimulation (TBS) is severely impaired in hippocampal field CA1 of young adult Fmr1 knock-out mice. The deficit was not associated with changes in postsynaptic responses to TBS, NMDA receptor activation, or levels of punctate glutamic acid decarboxylase-65/67 immunoreactivity. TBS-induced actin polymerization within dendritic spines was also normal. The LTP impairment was evident within 5 min of induction and, thus, may not be secondary to defects in activity-initiated protein synthesis. Protein levels for both brain-derived neurotrophic factor (BDNF), a neurotrophin that activates pathways involved in spine cytoskeletal reorganization, and its TrkB receptor were comparable between genotypes. BDNF infusion had no effect on baseline transmission or on postsynaptic responses to theta burst stimulation, but nonetheless fully restored LTP in slices from fragile X mice. These results indicate that the fragile X mutation produces a highly selective impairment to LTP, possibly at a step downstream of actin filament assembly, and suggest a means for overcoming this deficit. The possibility of a pharmacological therapy based on these results is discussed.

Key words: hippocampus; cofilin; actin; neurotrophin; LTP; mental retardation

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Received June 8, 2007; revised July 27, 2007; accepted Aug. 18, 2007.

Correspondence should be addressed to Dr. Julie C. Lauterborn, Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4292. Email: jclauter{at}uci.edu

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