Exercise-induced modulation of neuroinflammation in ageing.

Optimal performance of the central nervous system (CNS) depends on dynamic, multidirectional communication between different cell types both within and without the CNS to maintain the homeostatic environment. Ageing, in turn, is associated with CNS disequilibrium resulting in suboptimal functioning of its cells and potential cognitive impairment. Emerging evidence indicates that inter-organ communication influences the functioning of CNS cell types, which are subject to age- and environment-dependent alterations. Endurance exercise has specifically been demonstrated to have a marked impact on neuroimmune communications, particularly those involving microglia, the resident macrophages of the CNS parenchyma, as well as microglia-astrocyte interactions in rodents. Via its action on CNS glial cells, regular aerobic exercise has been shown to provide an adaptive advantage against perturbations to homeostasis, such as immunological challenge or ageing. In light of the accumulating evidence and evolutionary reasoning it may be argued that recurrent exercise-associated inter-organ signalling is necessary for the optimisation of glial function and hence CNS equilibrium. This, in turn, would imply that the absence of exercise-derived mediators and dysregulated inter-organ communication associated with a sedentary lifestyle may contribute to CNS dyshomeostasis, which is accelerated during ageing. As well as exploring the evidence of the impact of exercise on glial function, here we suggest potential next steps in identifying the mechanistic underpinnings of these effects and the potential importance of sex differences.

Investigation of MicroRNA-134 as a Target against Seizures and SUDEP in a Mouse Model of Dravet Syndrome.

Dravet syndrome (DS) is a catastrophic form of pediatric epilepsy mainly caused by noninherited mutations in the SCN1A gene. DS patients suffer severe and life-threatening focal and generalized seizures which are often refractory to available anti-seizure medication. Antisense oligonucleotides (ASOs) based approaches may offer treatment opportunities in DS. MicroRNAs are short noncoding RNAs that play a key role in brain structure and function by post-transcriptionally regulating gene expression, including ion channels. Inhibiting miRNA-134 (miR-134) using an antimiR ASO (Ant-134) has been shown to reduce evoked seizures in juvenile and adult mice and reduce epilepsy development in models of focal epilepsy. The present study investigated the levels of miR-134 and whether Ant-134 could protect against hyperthermia-induced seizures, spontaneous seizures and mortality (SUDEP) in F1.Scn1a(+/-)tm1kea mice. At P17, animals were intracerebroventricular injected with 0.1-1 nmol of Ant-134 and subject to a hyperthermia challenge at postnatal day (P)18. A second cohort of P21 F1.Scn1a(+/-)tm1kea mice received Ant-134 and were followed by video and EEG monitoring until P28 to track the incidence of spontaneous seizures and SUDEP. Hippocampal and cortical levels of miR-134 were similar between wild-type (WT) and F1.Scn1a(+/-)tm1kea mice. Moreover, Ant-134 had no effect on hyperthermia-induced seizures, spontaneous seizures and SUDEP incidence were unchanged in Ant-134-treated DS mice. These findings suggest that targeting miR-134 does not have therapeutic applications in DS.

Preeclampsia risk in oocyte donation versus double gamete donation pregnancies: A systematic review and meta-analysis.

The number of pregnancies achieved through gamete donation has escalated over the last decades. It has been hypothesized that double gamete donation pregnancies would have a higher risk of preeclampsia compared to single gamete donation pregnancies due to cumulative risk of preeclampsia in oocyte donation pregnancies and the separate risk associated with sperm donation. Therefore, a systematic review and meta-analysis was conducted to explore the association between double gamete donation pregnancies and the development of preeclampsia and gestational hypertension, comparing it with oocyte donation alone. A systematic search of five databases was conducted and meta-analysis was performed using a random-effects model. Of 795 screened articles, five met our selection criteria for a systematic review, and four were included in the meta-analysis.No statistically significant differences were found in the risk of preeclampsia between study subgroups (odds ratio [OR] 0.82; 95% confidence interval [95%CI] 0.29-2.36), even after subgroup analysis considering only high-quality studies (OR 1.30; 95%CI 0.61-2.76; I2 = 0%). Regarding gestational hypertension risk, neither the pooled analysis (OR 0.52; 95%CI 0.18-1.49; I2 = 84%) nor the high-quality studies subgroup analysis (OR 0.67; 95%CI 0.33-1.35; I2 = 0%) find any significant differences between oocyte donation or double gamete donation pregnancies. There appears to be little difference in gestational hypertension or preeclampsia risk between pregnancies resulting from double gamete donation and those from oocyte donation alone. Strict obstetrical surveillance should be considered standard of care for these women, in an attempt to perform early diagnosis and management of hypertensive disorders.

AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome.

Angelman syndrome (AS) is a severe neurodevelopmental disorder featuring ataxia, cognitive impairment, and drug-resistant epilepsy. AS is caused by mutations or deletion of the maternal copy of the paternally imprinted UBE3A gene, with current precision therapy approaches focusing on re-expression of UBE3A. Certain phenotypes, however, are difficult to rescue beyond early development. Notably, a cluster of microRNA binding sites was reported in the untranslated Ube3a1 transcript, including for miR-134, suggesting that AS may be associated with microRNA dysregulation. Here, we report levels of miR-134 and key targets are normal in the hippocampus of mice carrying a maternal deletion of Ube3a (Ube3a m-/p+ ). Nevertheless, intracerebroventricular injection of an antimiR oligonucleotide inhibitor of miR-134 (Ant-134) reduced audiogenic seizure severity over multiple trials in 21- and 42-day-old AS mice. Interestingly, Ant-134 also improved distance traveled and center crossings of AS mice in the open-field test. Finally, we show that silencing miR-134 can upregulate targets of miR-134 in neurons differentiated from Angelman patient-derived induced pluripotent stem cells. These findings indicate that silencing miR-134 and possibly other microRNAs could be useful to treat clinically relevant phenotypes with a later developmental window in AS.

Life-span characterization of epilepsy and comorbidities in Dravet syndrome mice carrying a targeted deletion of exon 1 of the Scn1a gene.

OBJECTIVE: Dravet Syndrome (DS) is a catastrophic form of paediatric epilepsy associated with multiple comorbidities mainly caused by mutations in the SCN1A gene. DS progresses in three different phases termed febrile, worsening and stabilization stage. Mice that are haploinsufficient for Scn1a faithfully model each stage of DS, although various aspects have not been fully described, including the temporal appearance and sex differences of the epilepsy and comorbidities. The aim of the present study was to investigate the epilepsy landscape according to the progression of DS and the long-term co-morbidities in the Scn1a(+/-)tm1Kea DS mouse line that are not fully understood yet. METHODS: Male and female F1.Scn1a(+/+) and F1.Scn1a(+/-)tm1Kea mice were assessed in the hyperthermia model or monitored by video electroencephalogram (vEEG) and wireless video-EEG according to the respective stage of DS. Long-term comorbidities were investigated through a battery of behaviour assessments in ~6 month-old mice. RESULTS: At P18, F1.Scn1a(+/-)tm1Kea mice showed the expected sensitivity to hyperthermia-induced seizures. Between P21 and P28, EEG recordings in F1.Scn1a(+/-)tm1Kea mice combined with video monitoring revealed a high frequency of SRS and SUDEP (sudden unexpected death in epilepsy). Power spectral analyses of background EEG activity also revealed that low EEG power in multiple frequency bands was associated with SUDEP risk in F1.Scn1a(+/-)tm1Kea mice during the worsening stage of DS. Later, SRS and SUDEP rates stabilized and then declined in F1.Scn1a(+/-)tm1kea mice. Incidence of SRS ending with death in F1.Scn1a(+/-)tm1kea mice displayed variations with the time of day and sex, with female mice displaying higher numbers of severe seizures resulting in greater SUDEP risk. F1.Scn1a(+/-)tm1kea mice ~6 month-old displayed fewer behavioural impairments than expected including hyperactivity, impaired exploratory behaviour and poor nest building performance. SIGNIFICANCE: These results reveal new features of this model that will optimize use and selection of phenotype assays for future studies on the mechanisms, diagnosis, and treatment of DS.