Submitted on June 15, 2006
Accepted on November 2, 2006
Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB induced potassium current
Tyler Kory Best1, Richard J Siarey2, and Zygmunt Galdzicki3*
1 Neuroscience Graduate Program, USUHS, Bethesda, Maryland, United States
2 Department of Anatomy, Physiology and Genetics, USUHS, School of Medicine, Bethesda, Maryland, United States
3 Department of Anatomy, Physiology and Genetics, Neuroscience Program, USUHS, School of Medicine, Bethesda, Maryland, United States
* To whom correspondence should be addressed. E-mail: zgaldzicki{at}usuhs.mil.
Down syndrome (DS) is the most common nonheritable cause of mental retardation. DS is the result of the presence of an extra chromosome 21 and its phenotype may be a consequence of overexpressed genes from that chromosome. One such gene is Kcnj6/Girk2, which encodes the G-protein coupled inward rectifying potassium channel subunit 2 (GIRK2). We have recently shown that the DS mouse model, Ts65Dn, overexpresses GIRK2 throughout the brain and in particular the hippocampus. Here, we report that this overexpression leads to a significant increase (~2 fold) in GABAB-mediated GIRK current in primary cultured hippocampal neurons. The dose response curves for peak and steady state GIRK current density is significantly shifted left towards lower concentrations of baclofen in Ts65Dn neurons compared to diploid controls, consistent with increased functional expression of GIRK channels. Stationary fluctuation analysis of baclofen-induced GIRK current from Ts65Dn neurons indicated no significant change in single channel conductance compared to diploid. However, significant increases in GIRK channel density was found in Ts65Dn neurons. In normalized baclofen-induced GIRK current and GIRK current kinetics no difference was found between diploid and Ts65Dn neurons, which suggest unimpaired mechanisms of interaction between GIRK channel and GABAB receptor. These results indicate that increased expression of GIRK2 containing channels have functional consequences which likely affect the balance between excitatory and inhibitory neuronal transmission.
