At current injections double the strength of the rheobase (which were applied in a subset of cells), the mean latency to the first AP (the chronaxie) did not differ (median and interquartile values: wild-type, 9.5 (6.8, 9.5) ms, n = 29; Ts65Dn, 8.7 (6.9, 10.5) ms, n = 15; p = 0.310, Mann Whitney U test). Although the increased excitability of Ts65Dn GCs was not accompanied by changes in AP accommodation, it was associated with changes in AP waveform

(Fig. 3A). The average amplitude, measured between the overshoot and the afterhyperpolarization (Bean, 2007) for the first three APs evoked at or just above rheobase, was larger Dabrafenib supplier by 4.4 mV in Ts65Dn cells (wild-type, 99.4 ± 1.4 mV, n = 33; Ts65Dn, 103.8 ± 1.1 mV, n = 20; p = 0.032, Student’s t-test). This was the result of a higher overshoot (by ~ 11%) without a change in afterhyperpolarization ( Fig. 3B). The larger APs in Ts65Dn GCs were also ~ 10% narrower (width at half amplitude: wild-type, Panobinostat concentration 714.9 ± 25.9 μs, n = 33; Ts65Dn, 643.5 ± 15.4 μs, n = 20; p = 0.045, Student’s t-test). It has

been shown previously that in wild-type GCs, membrane potential changes more slowly during the falling phase than the rising phase of the AP ( Brickley et al., 2007). Fig. 3C shows that this difference was maintained in Ts65Dn cells, indicating that the speeding of the APs was due to a proportionate increase in the maximum rates of rise and fall, of ~ 13% ( Fig. 3D). The finding that APs were faster in Ts65Dn cells, which have a longer membrane time constant because of their higher Cin and Rin, indicates that the speeding reflects changes in ion channel activity or distribution, which overcomes the slowing effect

of a longer membrane time constant on changes in membrane potential. It is known that there is a ~ 33% decrease in cerebellar volume and a 25–30% decrease in GC density in individuals with DS (Aylward et al., 1997, Baxter et al., 2000, Jernigan and Bellugi, 1990, Pinter et al., 2001 and Raz et al., 1995). We have found that in GCs of young adult Ts65Dn mice (P40–60), which replicate cerebellar changes in DS (20% shrinking of cerebellar volume, 14% narrowing of the granular layer, 24% drop in GC density) (Baxter et al., 2000 and Roper et al., 2006), the Y-27632 2HCl electrical properties of the surviving GCs are not identical to those of GCs in wild-type mice. As the paucity of GCs in Ts65Dn mouse cerebellum and DS cerebellum stems from impaired division of precursor cells (Haydar and Reeves, 2011), changes in the electrical properties of Ts65Dn GCs could potentially be caused by arrested or slower development that results in immature electrophysiological characteristics. Wild-type GCs undergo marked changes in excitability, input resistance and AP waveform during postnatal development (Brickley et al., 2001 and Cathala et al.