Numerous studies have demonstrated that the cognitive impairment exhibited by the TS mouse model of DS is due to an imbalance between excitatory and inhibitory neurotransmission, leading to excessive levels of neuronal inhibition. In particular, the marked reduction in LTP in the CA1 and DG areas of the hippocampus has been associated with enhanced GABA-mediated inhibition, as the impairments in synaptic plasticity and cognitive disturbances could be rescued in the TS mouse by BS-181 hydrochloride administering various antagonists or negative allosteric modulators of the GABAA receptor. Consistent with the increased levels of GABAergic synaptic proteins in the cortex and hippocampus of TS mice, in this study, we found enhanced expression of GAD65/67, which is a marker of GABAergic synapses, and reduced expression of VGLUT, which is a marker of glutamatergic synapses. Removing one copy of the Dyrk1A gene reduced GAD65/67 and enhanced VGLUT expression, respectively, to levels similar to those of euploid animals. Nimodipine Additional support for the role of Dyrk1A in the enhanced inhibition comes from a recent study that assessed the contribution of Dyrk1A gene dosage to this enhanced inhibition. This study demonstrated that increased dosage of Dyrk1A in mBACtgDyrk1a, Ts65Dn and Dp 1Yey mice carrying 3 copies of this gene led to an increased number and signal intensity of two markers of GABAergic synapses, GAD67 and VGAT. These authors propose that the increase in GAD67 staining in mBACtgDyrk1a mice could be indicative of an increase in the proportion of neurons that acquire a GABAergic phenotype during neuronal differentiation. In contrast, Dyrk1A mice, which carry one functional copy of this gene, exhibited reduced expression of this inhibitory synapse marker. In addition, as observed in the present study, these authors also found increased expression of the VGLUT1 marker of excitatory synapses in the mouse models bearing three copies of Dyrk1A in comparison to euploid mice. These results provide additional support for the role of Dyrk1A overexpression in the overinhibition found in Ts65Dn mice.