Reduced cortical BDNF expression and aberrant memory in Carf knock-out mice.
Transcription factors are a key point of convergence between the cell-intrinsic and extracellular signals that guide synaptic development and brain plasticity. Calcium-response factor (CaRF) is a unique transcription factor first identified as a binding protein for a calcium-response element in the gene encoding brain-derived neurotrophic factor (Bdnf). We have now generated Carf knock-out (KO) mice to characterize the function of this factor in vivo. Intriguingly, Carf KO mice have selectively reduced expression of Bdnf exon IV-containing mRNA transcripts and BDNF protein in the cerebral cortex, whereas BDNF levels in the hippocampus and striatum remain unchanged, implicating CaRF as a brain region-selective regulator of BDNF expression. At the cellular level, Carf KO mice show altered expression of GABAergic proteins at striatal synapses, raising the possibility that CaRF may contribute to aspects of inhibitory synapse development. Carf KO mice show normal spatial learning in the Morris water maze and normal context-dependent fear conditioning. However they have an enhanced ability to find a new platform location on the first day of reversal training in the water maze and they extinguish conditioned fear more slowly than their wild-type littermates. Finally, Carf KO mice show normal short-term (STM) and long-term memory (LTM) in a novel object recognition task, but exhibit impairments during the remote memory phase of testing. Together, these data reveal novel roles for CaRF in the organization and/or function of neural circuits that underlie essential aspects of learning and memory.
Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Kelli A
KA
McDowell
Ashley N
AN
Hutchinson
Sarah J E
SJ
Wong-Goodrich
Matthew M
MM
Presby
Dan
D
Su
Ramona M
RM
Rodriguiz
Krystal C
KC
Law
Christina L
CL
Williams
William C
WC
Wetsel
Anne E
AE
West
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D003213:Conditioning, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear; D005347:Fibroblasts; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency*; D014162:Transfection / Q000379:methods
D019208:Brain-Derived Neurotrophic Factor; C448259:Carf protein, mouse; D009419:Nerve Tissue Proteins; D014157:Transcription Factors