Fragile X Mental Retardation Protein Regulates Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells

Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA–binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs). We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3β. Dysregulation of GSK3β led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis

PreserFlo Microshunt for the management of intraocular pressure elevation in iridocorneal endothelial syndrome

Purpose: To report on a case of angle-closure glaucoma secondary to iridocorneal endothelial (ICE) syndrome effectively managed with the PreserFlo Microshunt. Observations: We report successful implantation of a PreserFlo Microshunt in a 57-year-old patient with secondary angle-closure glaucoma in the context of ICE syndrome. Following failure of medical therapy to adequately control intraocular pressure (IOP), the patient was consented for surgical intervention and underwent combined cataract surgery and PreserFlo Microshunt implantation. IOP at the last post-operative follow-up (5 months) was 12 mmHg with the patient on brinzolamide/timolol maleate (Azarga®). We report no complications in the post-operative period. Conclusions and importance: The PreserFlo Microshunt may be a promising option for patients with ICE syndrome who fail medical therapy. Implantation of this device was well tolerated in the presented case

Cognition, learning behaviour and hippocampal synaptic plasticity are not disrupted in mice over-expressing the cholesterol transporter ABCG1

Background: Cognitive deficits are a hallmark feature of both Down Syndrome (DS) and Alzheimer's Disease (AD). Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals. Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of Aβ peptides. The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis. Results: To assess the role of ABCG1 in DS-related cognition, we evaluated the cognitive performance of mice selectively over-expressing the ABCG1 gene from its endogenous regulatory signals. Both wild-type and ABCG1 transgenic mice performed equivalently on several behavioral tests, including measures of anxiety, as well as on reference and working memory tasks. No deficits in hippocampal CA1 synaptic plasticity as determined with electrophysiological studies were apparent in mice over-expressing ABCG1. Conclusion: These findings indicate that although ABCG1 may play a role in maintaining cellular or tissue cholesterol homeostasis, it is unlikely that excess ABCG1 expression contributes to the cognitive deficits in DS individuals.Cellular and Physiological Sciences, Department ofPathology and Laboratory Medicine, Department ofOther UBCNon UBCMedicine, Faculty ofReviewedFacult

Non-arteritic anterior ischemic and glaucomatous optic neuropathy: Implications for neuroretinal rim remodeling with disease severity.

PurposePost-acute non-arteritic ischemic optic neuropathy (NAION) and glaucomatous optic neuropathy (GON) can be difficult to differentiate clinically. Our objective was to identify optical coherence tomography (OCT) parameters to help differentiate these optic neuropathies.MethodsWe compared 12 eyes of 8 patients with NAION and 12 eyes of 12 patients with GON, matched for age and visual field mean deviation (MD). All patients underwent clinical assessment, automated perimetry (Humphrey Field Analyzer II; Carl Zeiss Meditec, Dublin, CA, USA), and OCT imaging (Spectralis OCT2; Heidelberg Engineering, Heidelberg, Germany) of the optic nerve head and macula. We derived the neuroretinal minimum rim width (MRW), peripapillary retinal nerve fibre layer (RNFL) thickness, central anterior lamina cribrosa depth, and macular retinal thickness.ResultsMRW was markedly thicker, both globally and in all sectors, in the NAION group compared to the GON group. There was no significant group difference in RFNL thickness, globally or in any sector, with the exception of the temporal sector that was thinner in the NAION group. The group difference in MRW increased with increasing visual field loss. Other differences observed included lamina cribrosa depth significantly greater in the GON group and significantly thinner central macular retinal layers in the NAION group. The ganglion cell layer was not significantly different between the groups.ConclusionsThe neuroretinal rim is altered in a dissimilar manner in NAION and GON and MRW is a clinically useful index for differentiating these two neuropathies. The fact that the difference in MRW between the two groups increased with disease severity suggests distinct remodelling patterns in response to differing insults with NAION and GON

Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning

Deficiency in fragile X mental retardation protein (FMRP) results in fragile X syndrome (FXS), an inherited form of intellectual disability. Despite extensive research, how FMRP deficiency contributes to the cognitive deficits in FXS is unclear. We have previously shown that Fmrp-null mice exhibit reduced adult hippocampal neurogenesis. Since Fmrp is also enriched in mature neurons, we explored the functional significance of Fmrp expression in neural stem and progenitor cells (aNSCs) and its role in adult neurogenesis. Here we show ablation of Fmrp in aNSCs via inducible gene recombination leads to reduced hippocampal neurogenesis in vitro and in vivo, as well as significantly impaired hippocampus-dependent learning in mice. Conversely, restoration of Fmrp expression specifically in aNSCs rescues these learning deficits. These data suggest that defective adult neurogenesis may contribute to the learning impairment seen in FXS, and these learning deficits can be rectified by delayed restoration of Fmrp specifically in aNSCs