Down syndrome (DS) mouse models exhibit cognitive deficits, and are used for studying the neuronal basis of DS pathology. To understand the differences in the physiology of DS model neurons, we used dissociated neuronal cultures from the hippocampi of Ts65Dn and Tc1 DS mice. Imaging of [Ca2+]i and whole cell patch clamp recordings were used to analyze network activity and single neuron properties, respectively. We found a decrease of ~30% in both fast (A-type) and slow (delayed rectifier) outward potassium currents. Depolarization of Ts65Dn and Tc1 cells produced fewer spikes than diploid cells. Their network bursts were smaller and slower than diploids, displaying a 40% reduction in δf/f0 of the calcium signals, and a 30% reduction in propagation velocity. Additionally, Ts65Dn and Tc1 neurons exhibited changes in the action potential shape compared to diploid neurons, with an increase in the amplitude of the action potential, a lower threshold for spiking, and a sharp decrease of about 65% in the after-hyperpolarization amplitude.Numerical simulations reproduced the DS measured phenotype by variations in the conductance of the delayed rectifier and A-type, but necessitated also changes in inward rectifying and M-type potassium channels and in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. We therefore conducted whole cell patch clamp measurements of M-type potassium currents, which showed a ~90% decrease in Ts65Dn neurons, while HCN measurements displayed an increase of ~65% in Ts65Dn cells. Quantitative real-time PCR analysis indicates overexpression of 40% of KCNJ15, an inward rectifying potassium channel, contributing to the increased inhibition. We thus find that changes in several types of potassium channels dominate the observed DS model phenotype.
Bibliographical noteFunding Information:
The authors thank Elizabeth Fisher for supplying the Tc1 mice and for many helpful suggestions and remarks, and Ofer Feinerman, Eitan Reuveny, Yaron Penn, Eyal Weinreb and Renaud Renault for very helpful discussions. We thank Shira Silberberg for the help in the genetic analysis, and Rinat Keren for help in Quantitative RT-PCR analysis. This work was partly supported by the Minerva Foundation (Munich, Germany) and by the Israel Science Foundation grant 1415/12 and the Clore Center for Biological Physics .
- Down syndrome
- Inward rectifiers
- Potassium channels
- Potassium currents
- Reduced excitability
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)