ain of a fully symptomatic EPM1 patient. Our data in young mice show a Vorapaxar web significant decrease in VGAT immunoreactivity along with the reduction of synapsin 1 positive pre-synaptic as well as gephyrin positive post-synaptic terminals, indicating that there PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19636622 are defects in GABAergic synapses in Cstb2/2 cerebellum already at the pre-symptomatic stage, before the loss of GABAergic interneurons is detectable. In contrast to the findings at P7, changes in the expression of genes reflecting synaptic functions by GO analysis are no longer observed at P30, or they may be hidden by significant enrichment for genes and pathways which pinpoint activation of inflammatory processes. Earlier reports from Cstb2/2 mice cerebella have shown microglial activation in presymptomatic mice followed by neuronal death and volume loss from two months of age onward. Therefore, elevated expression of inflammatory genes at P30 most likely reflect response to activated glial cells and neuroinflammation, which together with neuronal dysfunction and death has an important role in progression of the disease. Glial activation and oxidative stress might further promote the hyperexcitability in Cstb2/2 mice, as glial derived proinflammatory chemokines and cytokines, highly expressed also in P30 Cstb2/2 mice, have been found to reduce the seizure threshold and may thus contribute to recurrent excitation in epilepsy. In conclusion, we provide the first evidence of gene expression changes in pre-symptomatic and young symptomatic Cstb2/2 mice. Although there is no significant overlap with the differentially expresses genes at P7 and P30, GO analyses revealed alterations in several functional categories, which may contribute to EPM1. Our data indicate 
that pre- and post-synaptic changes in inhibitory GABAergic synapses could result in imbalance between excitation and inhibition in Cstb2/2 mouse cerebellum already before the disease symptoms occur, which may be augmented by inflammatory processes in the symptomatic phase. Glucokinase, the glucose sensor in hepatocytes and pancreatic b-cells, is the primary determinant of flux through glycolysis in both tissues and therefore plays a critical role in glucose homeostasis. Hepatic GCK is also regulated at the post-transcriptional level by the predominantly liver-specific glucokinase regulatory protein. GKRP is a competitive inhibitor of GCK with respect to glucose that localizes predominantly to the hepatocyte nucleus, sequestering GCK in the fasting state. In rodent model systems, increases in plasma glucose concentrations result in rapid hepatic glucose uptake, binding of glucose to Gck, subsequent dissociation of Gck from Gkrp, and nuclear export of active Gck. GKRP itself PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19640475 contains a single sugar-binding site capable of binding phosphate esters including fructose 1-phosphate and fructose 6-phosphate. F6P, a glycolytic intermediate that accumulates in the fasting state, enhances the interaction between GCK and GKRP. F1P, an intermediate in hepatic fructose breakdown, accumulates in the fructose-fed state and disrupts the GCKGKRP interaction. Accordingly, competitive binding of F1P or F6P to GKRP reinforces the glucose-dependent activity of hepatic GCK. The clinical relevance of mutations in GCK has long been appreciated. Heterozygous inactivating GCK mutations cause maturity-onset diabetes of the young, homozygous or compound heterozygous inactivating mutations cause permanent neonatal diabetes mellitus, and heterozygous activating