Key result
Ts65Dn Down syndrome mice exhibit ~2-fold higher GABAB-mediated GIRK currents vs diploid controls.
Increased expression of GIRK2 channels in the Ts65Dn Down syndrome mouse model leads to increased GABAB-mediated potassium currents, which likely affects the balance between excitatory and inhibitory neuronal transmission.
Enhanced GABAB-GIRK currents in Ts65Dn hippocampal neurons may contribute to DS phenotypes; leaves open whether GIRK2 modulation improves cognition in patients.
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 ( approximately 2-fold) in GABA(B)-mediated GIRK current in primary cultured hippocampal neurons. The dose response curves for peak and steady-state GIRK current density is significantly shifted left toward lower concentrations of baclofen in Ts65Dn neurons compared with 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 with 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 suggests unimpaired mechanisms of interaction between GIRK channel and GABA(B) receptor. These results indicate that increased expression of GIRK2 containing channels have functional consequences that likely affect the balance between excitatory and inhibitory neuronal transmission.
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Best et al. (2006) studied Down syndrome (mouse model). Ts65Dn mouse model (GIRK2 overexpression) vs. Diploid controls was evaluated on GABA(B)-mediated GIRK current in primary cultured hippocampal neurons. The Ts65Dn mouse model of Down syndrome exhibited an approximately 2-fold increase in GABA(B)-mediated GIRK current in primary cultured hippocampal neurons compared with diploid controls.
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