Interestingly, a recent report implicated Dyrk1A overexpression in the structural and functional anomalies of the prefrontal cortex. Therefore, the cognition-enhancing effects of normalization of the Dyrk1A expression level may be due to its effects on the hippocampal-prefrontal functional networks that support memoryrelated functions. TS +/+/+ mice are hyperactive under conditions that typically provoke caution in euploid mice, such as the open field test, and this hyperactivity is likely due to attentional deficits. In the present study, normalizing the level of Dyrk1A expression did not rescue this phenotype in TS mice; this lack of rescue might contribute to the incomplete improvement in cognitive function found in TS +/+/2 animals. In contrast to the present results, Ortiz-Abalia et al. demonstrated that normalization of the Dyrk1A expression level in the striatum via injection of an adenoassociated virus type 2-mediated Dyrk1A RNA inhibitor rescued motor deficits and attenuated hyperactivity in TgDyrk1A mice. In the present study, the lack of an effect of reducing the level of Dyrk1A expression on the hyperactivity of trisomic animals might indicate that other genes might play a role in this phenotypic alteration. Among the putative mechanisms that mediate the cognitiveenhancing effects of normalizing Dyrk1A expression are the improvement of synaptic efficacy and the amelioration of the neuromorphological deficits found in TS mice. Altered synaptic efficacy is a predominant mechanism underlying cognitive disturbances in trisomic animals. Hippocampal LTP, which is a substrate of learning and memory, is altered in TS mice, in other mouse models of DS and in mouse models that Cyclobenzaprine hydrochloride overexpress Dyrk1A. In this study, normalization of the Dyrk1A copy number in the TS mouse completely rescued hippocampal LTP, indicating that the extra copy of Dyrk1A in this mouse plays a role in the alteration in synaptic plasticity. Disulfiram Consistent with our results, pharmacological or genetic inhibition via administration of EGCG or injection of AAV2/1-shDyrk1A, respectively, enhances hippocampal LTP in TS mice.