Sleep Behavior and EEG Oscillations in Aged Dp(16)1Yey/+ Mice: A Down Syndrome Model.

Down syndrome (DS) results from the triplication of genes located on human chromosome 21 (Hsa21). Though many cognitive and behavioral impairments are associated with DS, sleep disturbances remain poorly understood despite being a reported phenotype in approximately 60% of individuals diagnosed with DS. In this study, sleep and electroencephalography (EEG) oscillations were recorded from aged (12-14 mos.) Dp(16)1Yey/+ mice (Dp16), a mouse model of DS. We observed disrupted sleep demonstrated by increased activity during the dark phase and increased time awake at the expense of NREM sleep compared to wild-type mice. In addition, we found that Dp16 mice display significant differences in relative EEG power distribution among oscillation frequencies in both sleep and awake states. These results in Dp16 mice are consistent with sleep disturbances found in individuals with DS, and the abnormal EEG oscillations in aged Dp16 mice suggest a potential role for GABAergic activity in these sleep and EEG abnormalities. These sleep and EEG data reflect underlying differences in neuronal activity at the network level and thus are causative agents rather than merely symptoms of DS.

Acute induction of conserved synaptic signaling pathways in Drosophila melanogaster.

Analyses of early molecular and cellular events associated with long-term plasticity remain hampered in Drosophila by the lack of an acute procedure to activate signal transduction pathways, gene expression patterns, and other early cellular events associated with long-term synaptic change. Here we describe the development and first use of such a technique. Bursts of neural activity induced in Drosophila comatosets and CaP60A Kumts mutants, with conditional defects in N-ethylmaleimide-sensitive fusion factor 1 and sarco-endoplasmic reticulum Ca2+ ATPase, respectively, result in persistent (>4 hr) activation of neuronal extracellular signal-regulated kinase (ERK). ERK activation at the larval neuromuscular junction coincides with rapid reduction of synaptic Fasciclin II; in soma, nuclear translocation of activated ERK occurs together with increased transcription of the immediate-early genes Fos and c/EBP (CCAAT element binding protein). The effect of "seizure-stimulation" on ERK activation requires neural activity and is mediated through activation of MEK (MAPK/erk kinase), the MAPKK (mitogen-activated protein kinase kinase) that functions upstream of ERK. Our results (1) provide direct proof for the conservation of synaptic signaling pathways in arthropods, (2) demonstrate the utility of a new genetic tool for analysis of synaptic plasticity in Drosophila, and (3) potentially enable new proteomic and genomic analyses of activity-regulated molecules in an important model organism.

Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism. The protein (FMRP) encoded by the fragile X mental retardation gene (FMR1), is an RNA-binding protein linked to translational control. Recently, in the Fmr1 knockout mouse model of FXS, dysregulated translation initiation signaling was observed. To investigate whether an altered signaling was also a feature of subjects with FXS compared to typical developing controls, we isolated total RNA and translational control proteins from lymphocytes of subjects from both groups (38 FXS and 14 TD). Although we did not observe any difference in the expression level of messenger RNAs (mRNAs) for translational initiation control proteins isolated from participant with FXS, we found increased phosphorylation of the mammalian target of rapamycin (mTOR) substrate, p70 ribosomal subunit 6 kinase1 (S6K1) and of the mTOR regulator, the serine/threonine protein kinase (Akt), in their protein lysates. In addition, we observed increased phosphorylation of the cap binding protein eukaryotic initiation factor 4E (eIF4E) suggesting that protein synthesis is upregulated in FXS. Similar to the findings in lymphocytes, we observed increased phosphorylation of S6K1 in brain tissue from patients with FXS (n = 4) compared to normal age-matched controls (n = 4). Finally, we detected increased expression of the cytoplasmic FMR1-interacting protein 2 (CYFIP2), a known FMRP interactor. This data verify and extend previous findings using lymphocytes for studies of neuropsychiatric disorders and provide evidence that misregulation of mTOR signaling observed in the FXS mouse model also occurs in human FXS and may provide useful biomarkers for designing targeted treatments in FXS.