Involvement of Potassium and Cation Channels in Hippocampal Abnormalities of Embryonic Ts65Dn and Tc1 Trisomic Mice

• Down syndrome model neurons display altered action potential shape, are less excitable and have decreased potassium currents.
• The data is accurately described by a numerical simulation that changes conductance of four potassium and the HCN currents.
• Measurements of the currents related to these four channels, and RT-pcr for a fifth (KCNJ15), confirm the numerical model.In Down syndrome (DS) cognitive function is impaired, leading us to use cultured hippocampal neuronal networks to investigate the cellular basis of its pathology. DS mouse model neurons are less excitable, produce fewer spikes and generate less network activity. Alterations in several types of potassium currents were detected in these neurons. Numerical simulation of a DS neuron successfully reproduced the experimental results. Beyond extending our understanding of neuronal function and pathology, the alterations in channel conductance can now be targeted with specific drugs so as to point to new directions in therapy of cognitive disabilities of DS.

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.