Over-expression of the DCLK gene transcript CARP decreases CA3/CA1 network excitability.
Products of the Doublecortin Like Kinase (DCLK) gene are implicated in cortical migration and hippocampal maturation during embryogenesis. However, one of its splice variants, called CaMK Related Peptide (CARP), is expressed during adulthood in response to neurological stimuli, such as kainic acid-induced seizures and BDNF-LTP. The function of this transcript of the DCLK gene is poorly understood. To elucidate its function during adulthood we have created transgenic mice with over-expression of CARP in the brain. To study potential functions of CARP in the hippocampus we performed an electrophysiological characterization of the CA3/CA1 network of transgenic and wild-type mice and showed that field excitatory post synaptic potentials (fEPSPs) are highly increased in transgenic mice, while population spike amplitudes (PSAs) remained equal between genotypes. Consequently, hippocampal CA3/CA1 network excitability was decreased in transgenic mice. In addition we show a 2-fold up-regulation of the Ca(2+)-binding protein calretinin and a down-regulation of Rapgef4, a guanine exchange factor for Rap1, in the hippocampus. Given previously established conditions during which CARP is induced and our current data, we propose that this DCLK gene product affects glutamatergic neuronal transmission in response to neurological stimuli.
Schenk
Geert J
GJ
Division of Medical Pharmacology, Leiden/Amsterdam Centre for Drug Research/Leiden University Medical Centre, Einsteinweg 55, Leiden, The Netherlands. g.j.schenk@LACDR.leidenuniv.nl
Werkman
Taco
T
Wadman
Wytse
W
Veldhuisen
Barbera
B
Dijkmans
Thomas F
TF
Blaas
Eva
E
Kegel
Linde
L
de Kloet
E Ron
ER
Vreugdenhil
Erno
E
D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000502:physiology*; D064032:Calbindin 2; D000089742:Doublecortin-Like Kinases; D004558:Electric Stimulation; D004827:Epilepsy / Q000139:chemically induced; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007608:Kainic Acid / Q000009:adverse effects; D051379:Mice; D009124:Muscle Proteins; D009474:Neurons / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D064030:S100 Calcium Binding Protein G / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic
C104844:Ankrd1 protein, mouse; C576511:Calb2 protein, mouse; D064032:Calbindin 2; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D064030:S100 Calcium Binding Protein G; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D007608:Kainic Acid