Glutamate released by activated microglia induces excitoneurotoxicity and may contribute to neuronal damage in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. In addition, tumor necrosis factor-␣ (TNF-␣) secreted from activated microglia may elicit neurodegeneration through caspasedependent cascades and silencing cell survival signals. However, direct neurotoxicity of TNF-␣ is relatively weak, because TNF-␣ also increases production of neuroprotective factors. Accordingly, it is still controversial how TNF-␣ exerts neurotoxicity in neurodegenerative diseases. Here we have shown that TNF-␣ is the key cytokine that stimulates extensive microglial glutamate release in an autocrine manner by up-regulating glutaminase to cause excitoneurotoxicity. Further, we have demonstrated that the connexin 32 hemichannel of the gap junction is another main source of glutamate release from microglia besides glutamate transporters. Although pharmacological blockade of glutamate receptors is a promising therapeutic candidate for neurodegenerative diseases, the associated perturbation of physiological glutamate signals has severe adverse side effects. The unique mechanism of microglial glutamate release that we describe here is another potential therapeutic target. We rescued neuronal cell death in vitro by using a glutaminase inhibitor or hemichannel blockers to diminish microglial glutamate release without perturbing the physiological glutamate level. These drugs may give us a new therapeutic strategy against neurodegenerative diseases with minimum adverse side effects.

Recent studies suggest that excitotoxicity may contribute to neuronal damage in neurodegenerative diseases including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. Activated microglia have been observed around degenerative neurons in these diseases, and they are thought to act as effector cells in the degeneration of neural cells in the central nervous system. Neuritic beading, focal bead-like swellings in the dendrites and axons, is a neuropathological sign in epilepsy, trauma, ischemia, aging, and neurodegenerative diseases. Previous reports showed that neuritic beading is induced by various stimuli including glutamate or nitric oxide and is a neuronal response to harmful stimuli. However, the precise physiologic significance of neuritic beading is unclear. We provide evidence that neuritic beading induced by activated microglia is a feature of neuronal cell dysfunction toward neuronal death, and the neurotoxicity of activated microglia is mediated through N-methyl-D-aspartate (NMDA) receptor signaling. Neuritic beading occurred concordant with a rapid drop in intracellular ATP levels and preceded neuronal death. The actual neurite beads consisted of collapsed cytoskeletal proteins and motor proteins arising from impaired neuronal transport secondary to cellular energy loss. The drop in intracellular ATP levels was because of the inhibition of mitochondrial respiratory chain complex IV activity downstream of NMDA receptor signaling. Blockage of NMDA receptors nearly completely abrogated mitochondrial dysfunction and neurotoxicity. Thus, neuritic beading induced by activated microglia occurs through NMDA receptor signaling and represents neuronal cell dysfunction preceding neuronal death. Blockage of NMDA receptors may be an effective therapeutic approach for neurodegenerative diseases.

Background:The aim of this meta-analysis was to investigate the prenatal, perinatal, and postnatal risk factors for children autism.Methods:PubMed, Embase, Web of Science were used to search for studies that examined the prenatal, perinatal, and postnatal risk factors for children autism. A fixed-effects model or random-effects model was used to pool the overall effect estimates.Results:Data from 37,634 autistic children and 12,081,416 nonautistic children enrolled in 17 studies were collated. During the prenatal period, the factors associated with autism risk were maternal and paternal age≥35 years, mother's and father's race: White and Asian, gestational hypertension, gestational diabetes, maternal and paternal education college graduate+, threatened abortion, and antepartum hemorrhage. During perinatal period, the factors associated with autism risk were caesarian delivery, gestational age≤36 weeks, parity≥4, spontaneous labor, induced labor, no labor, breech presentation, preeclampsia, and fetal distress. During the postnatal period, the factors associated with autism risk were low birth weight, postpartum hemorrhage, male gender, and brain anomaly. Parity≥4 and female were associated with a decreased risk of autism. In addition, exposure to cigarette smoking, urinary infection, mother's and father's race: Black and Hispanic, mother's country of birth outside Europe and North America, umbilical cord around neck, premature membrane rupture, 5-minutes Apgar score<7, and respiratory infection were not associated with increased risk of autism.Conclusion:The present meta-analysis confirmed the relation between some prenatal, perinatal, and postnatal factors with autism. All these factors were examined individually, thus it was still unclear that whether these factors are causal or play a secondary role in the development of autism. Further studies are needed to verify our findings, and investigate the effects of multiple factors on autism, rather than the single factor.

Interferon-gamma (IFN-gamma) is a proinflammatory cytokine that plays a pivotal role in pathology of diseases in the central nervous system (CNS), such as multiple sclerosis. However, the direct effect of IFN-gamma on neuronal cells has yet to be elucidated. We show here that IFN-gamma directly induces neuronal dysfunction, which appears as dendritic bead formation in mouse cortical neurons and enhances glutamate neurotoxicity mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptors but not N-methyl-D-aspartate receptors. In the CNS, IFN-gamma receptor forms a unique, neuron-specific, calcium-permeable receptor complex with AMPA receptor subunit GluR1. Through this receptor complex, IFN-gamma phosphorylates GluR1 at serine 845 position by JAK1.2/STAT1 pathway, increases Ca(2+) influx and following nitric oxide production, and subsequently decreases ATP production, leading to the dendritic bead formation. These findings provide novel mechanisms of neuronal excitotoxicity, which may occur in both inflammatory and neurodegenerative diseases in the CNS.

Accumulation of activated microglia and reactive astrocytes is observed around degenerating neurons in various inflammatory or degenerative disorders in the central nervous system. These reactive glial cells may play either neurotoxic or neuroprotective roles. In this study, we examined the effects of glia-derived cytokines on neuronal degeneration and regeneration. Neuron-rich cultures were stimulated with supernatant of microglia and astrocytes stimulated with LPS, or a various concentrations of recombinant cytokines. Neurotoxicity was evaluated by an MTS assay. Neuronal damage was also evaluated by a frequency of dendritic beading, which was found to be an early feature of neuronal damage toward cell death. Effects of the cytokines on production of neurotrophic factors by astrocytes were also examined by RT-PCR for the expression of mRNA. Supernatant of LPS-stimulated microglia induced neuronal cell death. However, all the recombinant cytokines examined did not induce cell death, while IFNgamma and TNFalpha induced dendrite beading, an early feature of neuronal damage. IL-1beta and TNFalpha enhanced the production of neurotrophic factors by astrocytes. These observations suggest that glial cell-derived cytokines may synergistically function in neuronal degeneration with other toxic factors produced by activated microglia, and that some of them may also function in regeneration by inducing neurotrophic factors.

No abstract

Previous studies have indicated an association between iodine excess and increased incidence of thyroid dysfunction in adults. However, there have been few studies on how the intake of excessive iodine affects thyroid function in children. The objective of this study was to assess the effects of a long-term exposure to excessive iodine on thyroid dysfunction in children. Urinary iodine concentration (UIC) and thyroid function in 371 children from a high iodine (HI) area (water iodine: 150-963 μg/L) and 150 children from an adequate iodine (AI) area (water iodine: 12.8-50.9 μg/L) were measured. The water iodine concentration in the HI area was higher than that in the AI area (P < 0.001) and the median urinary iodine concentration of children in the HI area was 1030 μg/L, which was 8.6 times that of children in the AI area (123 μg/L) (P < 0.001). Children in the HI area had a higher concentration of sensitive thyroid stimulating hormone and higher positivity of both thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb). The prevalence of thyroid diseases was higher in HI area children than that in AI area children (P = 0.000), especially subclinical hypothyroidism (SCH; P = 0.004). A body mass index (BMI) of ≥ 22.3 kg/m(2) was associated with the incidence of SCH (OR: 5.51; 95% CI: 1.52, 19.9; P = 0.009). UIC ≥ 600 μg/L (OR: 3.62; 95% CI: 1.22, 10.8; P = 0.024) and TPOAb or TGAb-positivity (Ab+ OR: 6.48; 95% CI: 1.78, 23.6; P = 0.005) in children were significantly and independently associated with SCH. Interactions between UIC ≥ 800 μg/L and Ab+ (P-interaction = 0.004) were found. Furthermore, increased thyroid volume was correlated with higher UIC (β = 0.22; P = 0.002). Excessive iodine intake in children in HI areas is associated with impaired thyroid function; UIC ≥ 600 μg/L and Ab+ are the risk factors for SCH. Effective measures need to be taken for reducing excessive iodine intake.

No abstract