It is thought that one role of GCs is to filter LGK 974 the quantity of information conveyed to the cerebellum by MFs before passing it on to PCs and inhibitory interneurons (Arenz et al., 2009). This role is favored by a relatively low input resistance of the GCs, which dampens their excitability so that closely-timed inputs from one or more MFs are usually necessary to evoke GC firing (Cathala et al., 2003, D’Angelo et al., 1995 and Hamann et al., 2002). Our finding that GCs in Ts65Dn mice are more excitable predicts weaker

sparsification of MF signals (Hamann et al., 2002), as activation of fewer MF inputs would be needed to evoke GC firing. In addition, the increased amplitude

and speeding of GC APs that we have observed may subtly modify the characteristics of glutamate release at downstream synapses between GC axons (parallel fibers) and PCs. These predictions need to be investigated experimentally, as changes in other properties, such as the probability of glutamate release from MFs and the amplitude and kinetics of excitatory postsynaptic PI3K inhibitor currents (EPSCs), may mitigate the impact of enhanced GC excitability on MF–GC information transfer. A detailed study of synaptic transmission in the CA3 area of cultured or acute hippocampal slices of, respectively, P5 and P13–16 Ts65Dn mice revealed complex changes in excitatory and inhibitory very synaptic transmission (Hanson et al., 2007). These included an increase in the number of excitatory synapses between CA3 pyramidal neurons and a decrease in the percentage of these synapses that was silent, a reduction in the amplitude of EPSCs at the active synapses, a diminished number of excitatory MF inputs and a reduction in inhibitory input from interneurons. The impact of the changes in excitability and AP waveform that we

have observed in Ts65Dn GCs on cerebellar function in humans with DS is unclear. If such changes accompany the decrease in GC number that occurs in all people with DS, they may result in altered GC signaling to downstream PCs that plays a part in the motor dysfunction displayed by most individuals with DS. Alternatively, such changes may compensate for the loss of GCs and minimize the degree of motor deficit that would otherwise occur. Different studies report either the presence (Costa et al., 1999 and Turner et al., 2001) or absence (Baxter et al., 2000, Escorihuela et al., 1995, Hyde et al., 2001 and Klein et al., 1996) of motor impairment inTs65Dn mice, making it difficult to ascribe roles for changes in GC number or electrophysiology to cerebellar dysfunction.