Neuronal hyperexcitability in the Tg2576 mouse model of Alzheimer's disease - the influence of sleep and noradrenergic transmission.

The link between Alzheimer's disease (AD) and network hypersynchrony - manifesting as epileptic activities - received considerable attention in the past decade. However, several questions remain unanswered as to its mechanistic underpinnings. Therefore, our objectives were (1) to better characterise epileptic events in the Tg2576 mouse model throughout the sleep-wake cycle and disease progression via electrophysiological recordings and (2) to explore the involvement of noradrenergic transmission in this pathological hypersynchrony. Over and above confirming the previously described early presence and predominance of epileptic events during rapid-eye-movement (REM) sleep, we also show that these events do not worsen with age and are highly phase-locked to the section of the theta cycle during REM sleep where hippocampal pyramidal cells reach their highest firing probability. Finally, we reveal an antiepileptic mechanism of noradrenergic transmission via α1-adrenoreceptors that could explain the intriguing distribution of epileptic events over the sleep-wake cycle in this model, with potential therapeutic implications in the treatment of the epileptic events occurring in many AD patients.

Early disruption of parvalbumin expression and perineuronal nets in the hippocampus of the Tg2576 mouse model of Alzheimer's disease can be rescued by enriched environment.

Recent findings show that parvalbumin (PV) interneuron function is impaired in Alzheimer's disease (AD), and that this impairment in PV function can be linked to network dysfunction and memory deficits. PV cells are often associated with a specific extracellular matrix, the perineuronal net (PNN). PNNs are believed to protect PV cell integrity, and whether the amyloidopathy affects PNNs remains unclear. Here, we evaluated the number of PV cells with and without PNNs in the hippocampus of the Tg2576 mouse model of AD at different stages of the disease. We show a deficit of PV+ and/or PV+/PNN+ cells in the areas CA1, CA2, and CA3 in Tg2576 as young as 3 months of age. Importantly, transient exposure to an enriched environment, which has proven long-lasting beneficial effects on memory in AD subjects, rescues the PV/PNN cell number deficits. We conclude that cognitive improvements induced by enriched environment in AD mouse models could be supported by a remodeling of hippocampal PV cell network and their PNNs.

Environmental enrichment does not influence hypersynchronous network activity in the Tg2576 mouse model of Alzheimer's disease.

The cognitive reserve hypothesis claims that the brain can overcome pathology by reinforcing preexistent processes or by developing alternative cognitive strategies. Epidemiological studies have revealed that this reserve can be built throughout life experiences as education or leisure activities. We previously showed that an early transient environmental enrichment (EE) durably improves memory performances in the Tg2576 mouse model of Alzheimer's disease (AD). Recently, we evidenced a hypersynchronous brain network activity in young adult Tg2576 mice. As aberrant oscillatory activity can contribute to memory deficits, we wondered whether the long-lasting memory improvements observed after EE were associated with a reduction of neuronal network hypersynchrony. Thus, we exposed non-transgenic (NTg) and Tg2576 mice to standard or enriched housing conditions for 10 weeks, starting at 3 months of age. Two weeks after EE period, Tg2576 mice presented similar seizure susceptibility to a GABA receptor antagonist. Immediately after and 2 weeks after this enrichment period, standard and enriched-housed Tg2576 mice did not differ with regards to the frequency of interictal spikes on their electroencephalographic (EEG) recordings. Thus, the long-lasting effect of this EE protocol on memory capacities in Tg2576 mice is not mediated by a reduction of their cerebral aberrant neuronal activity at early ages.

Early onset of hypersynchronous network activity and expression of a marker of chronic seizures in the Tg2576 mouse model of Alzheimer's disease.

Cortical and hippocampal hypersynchrony of neuronal networks seems to be an early event in Alzheimer's disease pathogenesis. Many mouse models of the disease also present neuronal network hypersynchrony, as evidenced by higher susceptibility to pharmacologically-induced seizures, electroencephalographic seizures accompanied by spontaneous interictal spikes and expression of markers of chronic seizures such as neuropeptide Y ectopic expression in mossy fibers. This network hypersynchrony is thought to contribute to memory deficits, but whether it precedes the onset of memory deficits or not in mouse models remains unknown. The earliest memory impairments in the Tg2576 mouse model of Alzheimer's disease have been observed at 3 months of age. We thus assessed network hypersynchrony in Tg2576 and non-transgenic male mice at 1.5, 3 and 6 months of age. As soon as 1.5 months of age, Tg2576 mice presented higher seizure susceptibility to systemic injection of a GABAA receptor antagonist. They also displayed spontaneous interictal spikes on EEG recordings. Some Tg2576 mice presented hippocampal ectopic expression of neuropeptide Y which incidence seems to increase with age among the Tg2576 population. Our data reveal that network hypersynchrony appears very early in Tg2576 mice, before any demonstrated memory impairments.

Inhaled corticosteroid-induced hair depigmentation in a child.

An Afro-Caribbean girl showed localized hair depigmentation during treatment with inhaled fluticasone propionate. Although skin depigmentation is common after topical use of corticosteroids, hair depigmentation has never been reported with inhaled corticosteroids. The mechanisms underlying corticosteroid-induced skin depigmentation are not completely understood, but accepted hypotheses suggest a direct cytotoxic effect, changes in ground substance, vasoconstriction, mechanical effects of edema, or a dysregulation of melanogenesis.

1P19Q loss but not IDH1 mutations influences WHO grade II gliomas spontaneous growth.

Mutations at the codon 132 in the isocitrate dehydrogenase 1 (IDH1) gene occur early, with a high frequency, in World Health Organization (WHO) grade II gliomas. We investigated the impact of IDH1 mutations on spontaneous glioma growth rate, known to be an early prognostic factor.The mean tumor diameter was assessed on the first MRI performed at diagnosis and on a second MRI, performed immediately before surgery, in a series of 64 WHO grade II gliomas. The patients did not undergo treatment before surgery. Because of a frequent association, we jointly analyzed the 1p19q co-deletion and IDH1 mutations effects on tumor velocity of diameter expansion (mm/year) during preoperative spontaneous growth period. 1p19q co-deletion had a significant slowing effect (p = 0.0133) on tumor growth estimated at -1.7760 ± 0.711 mm/year (95% CI -3.154, -0.366), whereas IDH1 mutations estimated effect of +0.036 ± 0.833 mm/year (95% CI -1.668; +1.596) was not significant (p = 0.9654). Our results provide first evidence that IDH1 mutations are not significantly involved in tumor growth rate. By contrast, we confirm that 1p19q co-deletion decreases growth velocity.