Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome.
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.
Lauterborn
Julie C
JC
Department of Anatomy and Neurobiology, University of California, Irvine, California 92697-4292, USA. jclauter@uci.edu
Rex
Christopher S
CS
Kramár
Eniko
E
Chen
Lulu Y
LY
Pandyarajan
Vijay
V
Lynch
Gary
G
Gall
Christine M
CM
D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D051338:Cofilin 1 / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
D000199:Actins; D019208:Brain-Derived Neurotrophic Factor; D051338:Cofilin 1; D051860:Fragile X Messenger Ribonucleoprotein 1; D016194:Receptors, N-Methyl-D-Aspartate; C497684:Fmr1 protein, mouse