Association Between 5-HTTLPR Polymorphism and the Risk of Autism: A Meta-Analysis Based on Case-Control Studies

Background: Recently, many case-control studies have reported the association between 5-HTTLPR polymorphism and autism risk. However, the results are inconclusive and conflicting. To investigate the genetic association of 5-HTTLPR polymorphism and autism risk, we conducted a comprehensive meta-analysis based on previous case-control studies.Methods: Literature search was performed through PubMed, Embase, Web of Knowledge and CNKI databases until June 27, 2018. The strength of the association was assessed by relative risk (RR) and its corresponding 95% confidence interval (CI). Fixed or random effect model was selected based on the results of heterogeneity test. Further, subgroup analyses were conducted to explore the association of 5-HTTLPR polymorphism and autism risk in different population.Results: Eleven studies with 930 cases and 1234 controls were identified. Although there was a significant association between 5-HTTLPR polymorphism and autism risk under the dominant model after removing the studies causing heterogeneity, the significance did not exist after Bonferroni's correction. Subgroup analyses also showed similar results after Bonferroni's correction. In addition, there was no obvious publication bias in our meta-analysis.Conclusions: Our present meta-analysis does not support a direct effect of 5-HTTLPR polymorphism on autism risk according to present results. Further analyses of the effect of genetic networks and more well designed studies with larger sample size are required

The Liver X Receptor Agonist TO901317 Ameliorates Behavioral Deficits in Two Mouse Models of Autism

Autism spectrum disorder (ASD) is a developmental disability characterized by social deficits and repetitive stereotyped behaviors. There are currently no drugs available for the treatment of the core symptoms of ASD, suggesting an urgent need for new therapeutic strategies. The neurobiology of autism is complex, but emerging research indicates that defects in hippocampal neurogenesis are associated with ASD in both humans and mouse models of ASD, leading to the suggestion that restoring neurogenesis may be a novel therapeutic approach for ASD. Here, we found that postnatal treatment with TO901317 (TO), a potent liver X receptor (LXR) agonist, typically activated LXRβ and its target genes in the hippocampus, and alleviated the social deficits and stereotypical behaviors in BTBR T+ tf/J (BTBR) and valproic acid (VPA)-induced mouse models. In addition, we further confirmed that TO postnatal treatment also rescued the inhibition of adult hippocampal neurogenesis in these two models. In summary, our study suggests that LXR agonist targeting hippocampal neurogenesis may represent a novel potential therapy for ASD

Protective effects of resveratrol on the inhibition of hippocampal neurogenesis induced by ethanol during early postnatal life

AbstractEthanol (EtOH) exposure during early postnatal life triggers obvious neurotoxic effects on the developing hippocampus and results in long-term effects on hippocampal neurogenesis. Resveratrol (RSV) has been demonstrated to exert potential neuroprotective effects by promoting hippocampal neurogenesis. However, the effects of RSV on the EtOH-mediated impairment of hippocampal neurogenesis remain undetermined. Thus, mice were pretreated with RSV and were later exposed to EtOH to evaluate its protective effects on EtOH-mediated toxicity during hippocampal development. The results indicated that a brief exposure of EtOH on postnatal day 7 resulted in a significant impairment in hippocampal neurogenesis and a depletion of hippocampal neural precursor cells (NPCs). This effect was attenuated by pretreatment with RSV. Furthermore, EtOH exposure resulted in a reduction in spine density on the granular neurons of the dentate gyrus (DG), and the spines exhibited a less mature morphological phenotype characterized by a higher proportion of stubby spines and a lower proportion of mushroom spines. However, RSV treatment effectively reversed these responses. We further confirmed that RSV treatment reversed the EtOH-induced down-regulation of hippocampal pERK and Hes1 protein levels, which may be related to the proliferation and maintenance of NPCs. Furthermore, EtOH exposure in the C17.2 NPCs also diminished cell proliferation and activated apoptosis, which could be reversed by pretreatment of RSV. Overall, our results suggest that RSV pretreatment protects against EtOH-induced defects in neurogenesis in postnatal mice and may thus play a critical role in preventing EtOH-mediated toxicity in the developing hippocampus

Epothilone B Benefits Nigral Dopaminergic Neurons by Attenuating Microglia Activation in the 6-Hydroxydopamine Lesion Mouse Model of Parkinson’s Disease

Parkinson’s disease (PD) is characterized by loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and a subsequent reduction in striatal DA levels. Recent studies have shown that systemic administration of subtoxic doses of epothilone B (EpoB), a microtubule stabilizing agent, enhances axonal regeneration. However, the underlying alterations in cellular mechanisms remain undetermined. In the present study, we investigated the neuroprotective effects of EpoB on DA neurons in mouse model of PD induced by 6-hydroxyDA (6-OHDA) and in vitro. The results indicated that EpoB improved behavioral deficits, protected the nigrostriatal dopaminergic projections and restored DA level in the striatum of mice exposed to 6-OHDA. Meanwhile, EpoB attenuated microglia activation in the SNc of PD mice. Furthermore, EpoB treatment ameliorated 6-OHDA induced cytotoxicity to MN9D dopaminergic cells in a co-culture transwell system of BV2/MN9D cells, and redistributed the cytoskeleton of microglial BV2 and caused the morphological transition, inhibited the polarization to the M1 phenotype by suppressing expression of pro-inflammatory factors including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α. Overall, our study suggested that EpoB treatment protects nigral DA neurons and projections through limiting the cytotoxicity of activated microglia in 6-OHDA lesioned mice

Rescue of Retinal Degeneration in rd1 Mice by Intravitreally Injected Metformin

Retinitis pigmentosa (RP) is a progressive hereditary retinal degenerative disease in which photoreceptor cells undergo degeneration and apoptosis, eventually resulting in irreversible loss of visual function. Currently, no effective treatment exists for this disease. Neuroprotection and inflammation suppression have been reported to delay the development of RP. Metformin is a well-tested drug used to treat type 2 diabetes, and it has been reported to exert beneficial effects in neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. In the present study, we used immunofluorescence staining, electroretinogram (ERG) recordings and RNA-Seq to explore the effects of metformin on photoreceptor degeneration and its mechanism in rd1 mice. We found that metformin significantly reduced apoptosis in photoreceptors and delayed the degeneration of photoreceptors and rod bipolar cells in rd1 mice, thus markedly improving the visual function of rd1 mice at P14, P18, and P22 when tested with a light/dark transition test and ERG. Microglial activation in the outer nuclear layer (ONL) of the retina of rd1 mice was significantly suppressed by metformin. RNA-Seq showed that metformin markedly downregulated inflammatory genes and upregulated the expression of crystallin proteins, which have been demonstrated to be important neuroprotective molecules in the retina, revealing the therapeutic potential of metformin for RP treatment. αA-crystallin proteins were further confirmed to be involved in the neuroprotective effects of metformin in a Ca2+ ionophore-damaged 661W photoreceptor-like cell line. These data suggest that metformin exerts a protective effect in rd1 mice via both immunoregulatory and new neuroprotective mechanisms