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Epilepsy is characterized by recurrent, spontaneous seizures and is a major contributor to the global burden of neurological disease. Although epilepsy can result from a variety of brain insults, in many cases the cause is unknown and, in a significant proportion of cases, seizures cannot be controlled by available treatments. Understanding the molecular alterations that underlie or are triggered by epileptogenesis would help to identify therapeutics to prevent or control progression to epilepsy. To this end, the moderate throughput technique of Reverse Phase Protein Arrays (RPPA) was used to profile changes in protein expression in a pilocarpine mouse model of acquired epilepsy. Levels of 54 proteins, comprising phosphorylation-dependent and phosphorylation-independent components of major signaling pathways and cellular complexes, were measured in hippocampus, cortex and cerebellum of mice at six time points, spanning 15 min to 2 weeks after induction of status epilepticus. Results illustrate the time dependence of levels of the commonly studied MTOR pathway component, pS6, and show, for the first time, detailed responses during epileptogenesis of multiple components of the MTOR, MAPK, JAK/STAT and apoptosis pathways, NMDA receptors, and additional cellular complexes. Also noted are time- and brain region- specific changes in correlations among levels of functionally related proteins affecting both neurons and glia. While hippocampus and cortex are primary areas studied in pilocarpine-induced epilepsy, cerebellum also shows significant time-dependent molecular responses.

Major efforts in Down syndrome (DS) research have been directed at the identification and functional characterization of genes encoded by human chromosome 21 (HSA21). In parallel with this, tissue samples and cell lines derived from individuals with DS have been examined for abnormalities in gene expression and cellular morphology, and mouse models of DS have been characterized for abnormalities at the molecular, cellular, electrophysiological, and behavioral level. One goal of such investigations has been the identification of effective targets for pharmacotherapies that can prevent or correct the abnormalities and, by extension to human clinical trials, prevent or lessen aspects of the cognitive deficits seen in people with DS. Because it is caused by an extra copy of an entire chromosome, DS has been considered by some as too complicated a genetic perturbation to be amenable to postnatal pharmacological interventions. However, recent data from experiments with one mouse model, the Ts65Dn, have clearly demonstrated that several pharmacological interventions can indeed rescue DS-relevant learning and memory deficits. Extension of mouse data to successful human clinical trials will be aided by understanding the molecular basis of successful drug treatments, that is, how increased expression of HSA21 genes perturbs molecular mechanisms that are targeted and rescued by specific drugs. Here, we review information on HSA21 genes, their expression and their likely contributions to the DS phenotype. We then describe results of a bioinformatics effort that integrates information on genes known to cause intellectual disability when mutated, the pathways in which these genes function, and how these pathways are impacted by HSA21 encoded proteins. This pathway approach to the molecular basis of ID in DS aids in understanding why some drug therapies have been successful in the Ts65Dn and in predicting whether these same drugs are likely to be successful in treating ID in DS. These data can be used to design new experiments and interpret information for prediction of additional targets for effective drug treatments., (Copyright © 2012 Elsevier B.V. All rights reserved.)