Pathology of Down Syndrome manifested in network and single neuron properties of hippocampal neuronal cultures

Background: Down Syndrome (DS) is the most common chromosomal abnormality in humans, with many phenotypic characteristics-mental retardation is probably the most prominent one. Embryonic hippocampal neuronal cultures from two mouse models (TC1 and Ts65Dn) for DS were compared to control littermate cultures to detect possible cellular phenotypes of DS. Network behaviour was assessed using calcium imaging, and whole cell patch clamp technique was used to measure differences in single cell properties. Results: Calcium imaging, measured with fluo4, revealed smaller amplitude, shorter duration network bursts, with no change in basal calcium level, which was measured using Fura-2. Baclofen, a GABA-B agonist, suppressed network bursts with lower concentration in DS networks than in control networks. In patch clamped neurons, the threshold for excitation, after-hyperpolarization (AHP) amplitude and input resistance were reduced, while spike height was increased in DS cells compared to controls. Following blockage of sodium currents we found that potassium currents (slow and fast) are reduced in DS cells. Network activity was different with electrophysiological tools as well: bursts were shorter, the total amount of time the network spent bursting was shorter, and network bursts were less synchronized. Most of the differences appeared in both mouse models. Conclusions: DS cells were different both in the basic cell properties and in the assembly into a network. The changes in spike properties, along with reduced potassium currents all point to changes in potassium channels. We speculate that this may be due to possible overexpression of two potassium channel regulators, KCNE1 and KCNE2, whose genes reside on chromosome 21. The altered network activity along with baclofen experiments may be caused by increased inhibition. Two types of inwardly rectifying potassium channels genes reside on chromosome 21: KCNJ6, KCNJ15, and may be the cause of this increased network inhibition.