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 Ca2+-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.

Research Highlights
► (1) We generated a novel mouse line with high levels of CARP mRNA throughout the brain.
► (2) Brain regions with CARP expression include the amygdala and hippocampus.
► (3) We show an electrophysiological phenotype of the CA3/CA1 network in these mice.
► (4) fEPSPs show a robust increase, whilst PSAs are equal in transgenic CARP mice and littermate controls.
► (5) We show differential expression of RapGef4 and Calretinin in CARP mouse hippocampus.