A novel role of circadian transcription factor DBP in hippocampal plasticity.
In neurons, a variety of extracellular stimuli are capable of inducing transcriptional events that underlie complex processes ranging from learning to disease. The mechanisms linking these long-lasting cellular modifications to behavior remain to be established. Here, we show by microarray analysis that hippocampal activation of glucagon-like peptide-1 receptor (GLP-1R), which is associated with improved learning and neuroprotection, results in suppression of the transcription factor DBP (albumin D-site-binding protein). Recombinant adeno-associated virus (rAAV) based gene expression of DBP in the hippocampus of adult rats caused upregulation of mRNAs encoding constituents of the molecular clock, and the DBP target gene, pyridoxal kinase. Behaviorally, DBP over expression inhibited spatial learning but not memory, and enhanced susceptibility to kainate-induced seizures. This phenotype was paralleled by the activation of MAP kinase in dendritic regions of hippocampal neurons in vivo. These data suggest that DBP may represent an important transcriptional link between GLP-1R activation and neuroplasticity in the hippocampus.
Klugmann
Matthias
M
Functional Genomics and Translational Neuroscience Laboratory, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand. m.klugmann@uni-hd.de
Leichtlein
Claudia B
CB
Symes
C Wymond
CW
Klaussner
Bettina C
BC
Brooks
Andrew I
AI
Young
Deborah
D
During
Matthew J
MJ
D000818:Animals; D001683:Biological Clocks / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D007608:Kainic Acid / Q000378:metabolism; D007858:Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D051381:Rats; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
C485975:DBP protein, rat; D004268:DNA-Binding Proteins; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D007608:Kainic Acid