A popular blood pressure drug also appears to reduce the stress of being born and curb symptoms of autism in rodents. Though critics say the findings may not apply to people, the work could reveal new understandings—and treatments—for the complex neurodevelopmental disorder.Our brains are naturally hyperactive in utero, at least according to rodent studies. High levels of chloride inside neurons keep these cells buzzing with electrical activity, which may promote rapid brain development and growth, says Yehezkel Ben-Ari, a neuroscientist at the biomedical research agency INSERM’s Mediterranean Institute of Neurobiology in Marseille, France, and acting CEO of Neurochlore, a company that develops treatments for developmental disorders. During labor, however, the release of a hormone called oxytocin causes chloride ion levels in cells to drop, calming these neurons down. That, in turn, appears to help babies deal with the stress of childbirth, Ben-Ari suggests.Because complications during labor have been associated with higher rates of autism, Ben-Ari and his colleagues speculate that this protective switch may not occur for babies who go on to develop the disorder. The team tested its hypothesis in two separate rodent models of autism. One group of mice had the most common genetic mutation associated with the human disorder—it’s seen in 2% to 6% of people with autism—while a group of rats was exposed in utero to sodium valproate, an epilepsy drug known to significantly increase risk of autism in children whose mothers take the medication. Although there’s no way to create a truly “autistic” animal, these mice and rats have social deficits similar to those seen in people with the condition: Some lack interest in new companions, for example, and don’t react—squeak in distress—as much when separated from their mothers.Sign up for our daily newsletterGet more great content like this delivered right to you!Country *AfghanistanAland IslandsAlbaniaAlgeriaAndorraAngolaAnguillaAntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustraliaAustriaAzerbaijanBahamasBahrainBangladeshBarbadosBelarusBelgiumBelizeBeninBermudaBhutanBolivia, Plurinational State ofBonaire, Sint Eustatius and SabaBosnia and HerzegovinaBotswanaBouvet IslandBrazilBritish Indian Ocean TerritoryBrunei DarussalamBulgariaBurkina FasoBurundiCambodiaCameroonCanadaCape VerdeCayman IslandsCentral African RepublicChadChileChinaChristmas IslandCocos (Keeling) IslandsColombiaComorosCongoCongo, The Democratic Republic of theCook IslandsCosta RicaCote D’IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDenmarkDjiboutiDominicaDominican RepublicEcuadorEgyptEl SalvadorEquatorial GuineaEritreaEstoniaEthiopiaFalkland Islands (Malvinas)Faroe IslandsFijiFinlandFranceFrench GuianaFrench PolynesiaFrench Southern TerritoriesGabonGambiaGeorgiaGermanyGhanaGibraltarGreeceGreenlandGrenadaGuadeloupeGuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHeard Island and Mcdonald IslandsHoly See (Vatican City State)HondurasHong KongHungaryIcelandIndiaIndonesiaIran, Islamic Republic ofIraqIrelandIsle of ManIsraelItalyJamaicaJapanJerseyJordanKazakhstanKenyaKiribatiKorea, Democratic People’s Republic ofKorea, Republic ofKuwaitKyrgyzstanLao People’s Democratic RepublicLatviaLebanonLesothoLiberiaLibyan Arab JamahiriyaLiechtensteinLithuaniaLuxembourgMacaoMacedonia, The Former Yugoslav Republic ofMadagascarMalawiMalaysiaMaldivesMaliMaltaMartiniqueMauritaniaMauritiusMayotteMexicoMoldova, Republic ofMonacoMongoliaMontenegroMontserratMoroccoMozambiqueMyanmarNamibiaNauruNepalNetherlandsNew CaledoniaNew ZealandNicaraguaNigerNigeriaNiueNorfolk IslandNorwayOmanPakistanPalestinianPanamaPapua New GuineaParaguayPeruPhilippinesPitcairnPolandPortugalQatarReunionRomaniaRussian FederationRWANDASaint Barthélemy Saint Helena, Ascension and Tristan da CunhaSaint Kitts and NevisSaint LuciaSaint Martin (French part)Saint Pierre and MiquelonSaint Vincent and the GrenadinesSamoaSan MarinoSao Tome and PrincipeSaudi ArabiaSenegalSerbiaSeychellesSierra LeoneSingaporeSint Maarten (Dutch part)SlovakiaSloveniaSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSvalbard and Jan MayenSwazilandSwedenSwitzerlandSyrian Arab RepublicTaiwanTajikistanTanzania, United Republic ofThailandTimor-LesteTogoTokelauTongaTrinidad and TobagoTunisiaTurkeyTurkmenistanTurks and Caicos IslandsTuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVenezuela, Bolivarian Republic ofVietnamVirgin Islands, BritishWallis and FutunaWestern SaharaYemenZambiaZimbabweI also wish to receive emails from AAAS/Science and Science advertisers, including information on products, services and special offers which may include but are not limited to news, careers information & upcoming events.Required fields are included by an asterisk(*)Using electrodes to measure the flow of current in and out of neurons of the rodent fetuses in utero and after they were born, the researchers found that chloride levels were higher than average in the embryonic brain cells of the “autistic” animals, and stayed that way through adulthood. EEG tests showed abnormally large and powerful oscillations in the rodents’ hippocampi, where memories are processed and stored, suggesting that brain activity was not being properly controlled. Normal rats and mice, in contrast, had high levels of chloride inside their neurons in utero, but these dropped soon after delivery and their brain activity appeared normal.Next, the team tested whether bumetanide, a drug that blocks chloride transport channels in neurons and is frequently prescribed for high blood pressure, could lower chloride and restore normal neuron function in the autistic rodents. In 2012, the team had conducted a small clinical trial with the drug, finding that it modestly improved social behaviors in children with mild autism. Ben-Ari and his colleagues laced the drinking water of pregnant mice and rats with the bumetanide, then once again measured their offspring’s neuronal chloride levels and excitability before and after birth. Chloride levels and brain activity were restored to approximately normal levels in both groups, the researchers report online today in Science. In addition, adult autistic mice treated with the drug resumed more normal social behaviors.Ben-Ari believes the new work underscores the value of ongoing clinical trials of bumetanide in children who have already begun to show symptoms of autism. He does not foresee that the drug will be administered prenatally to pregnant mothers, however, as there is no way to diagnose autism in the womb.Others remain cautious: Because human brains develop at vastly different rates from rodent brains—3 to 4 weeks of development in people is equivalent to a day or less in mice, for example—the team’s observations may not hold in human autism, notes Emanuel DiCicco-Bloom, a neuroscientist at Rutgers University’s Robert Wood Johnson Medical School in Piscataway, New Jersey.Larry Young, a neuroscientist at Emory University in Atlanta, shares DiCicco-Bloom’s concern that the authors of the new study are too quick to equate rodent models with humans, but says it is “very exciting” to see evidence that hormonal signaling between mother and child during birth can make changes to brain circuitry that last a long time.Overall, the study is “pretty awesome,” DiCicco-Bloom says. “I don’t think that anyone would have predicted” that chloride levels would be abnormally high in both models of autism, or that just one treatment with bumetanide before birth could correct them, he says. Although there is no way to diagnose or treat autism before birth in humans, he says, a host of obstetrical complications have been associated with higher risk of autism and intellectual disability. “This could be one of the mechanisms by which that occurs,” he says.”*Correction, 6 February, 3:55 p.m.: This item has been modified to reflect the fact that both mice and rats were used in the autism models.
Share5TweetShare1Email6 SharesDetroit Institute of Art ~ Diego Rivera Mura / VasenkaPhotographyMay 6, 2016; Bloomberg BNA and Forbes, “Opinion”Does the “Grand Bargain” that rescued Detroit from bankruptcy provide a way forward for other cities struggling with similar and huge economic problems? Howard Husock, vice president for research and publications at the Manhattan Institute, suggests that it could for cities “straining under the burden of ‘legacy costs’ and a paralyzed politics that’s been unable to deal with them, even as city services erode.”Due to an underfunded municipal pension system, a stagnant local economy, a shrinking tax base, and an inability to adequately provide city services, Detroit became the first major American city in modern times to declare bankruptcy. The Detroit agreement allowed Detroit to eliminate $7 billion of accumulated debt, reinvest more than $1 billion dollars into neglected public services, reduce its pension obligations to retirees, and cut payments to bondholders.What made the Detroit solution unique—though, as Husock believes, perhaps replicable—was the key role the philanthropic community played. Initially motivated by the looming loss of $1 billion of city owned artwork, twelve major Detroit-based foundations stepped forward and committed $268.7 million (net-present-value dollars, 2015), motivating the state government to contribute $194.8 million and retirees and unions to agree to $1.33 billion in reduced pensions. In an interview with NPR News in November 2014, Darren Walker, president of the Ford Foundation, described the motivation for the foundation’s intervention:We’re not in the business of solving bankruptcies, but we do solve big problems and work with leaders at the city level and the community level, public and private sectors, to help solve community problems. […] This was a complicated $20 billion bankruptcy with thousands of creditors and many contested issues. But our focus, which was on saving the Detroit Institute of the Arts and ameliorating the situation for the workers of the city, particularly those retirees under the pension fund…that was what we were able to help accomplish.Key to the deal was the privatization of the world-renowned Detroit Institute of Arts, which the city essentially sold to a private nonprofit established to run it. The funding for purchasing the institute came from large foundations such as Kresge and Ford, and the proceeds contributed to the pension bailout. The Manhattan Institute said that there are sufficient philanthropic assets in Chicago, St. Louis, Cleveland, and Buffalo to achieve the same result.From Husock’s perspective, other cities should study Detroit’s model carefully because their foundations have the necessary resources to make a significant contribution to a “bargain.” However, Bloomberg News reports that academics and attorneys specializing in municipal finance doubt that the public pension overhaul proposal by the Manhattan Institute based on that model could remedy the significant retirement liabilities. The experts also disagreed with the Manhattan Institute’s claim that regional and national foundations would be willing to be a “piggy bank” for cities’ public-sector pension debts.Christopher R. Berry, director of the Center for Municipal Finance at the University of Chicago’s Harris School of Public Policy, told Bloomberg that the Manhattan Institute’s analysis reflects a misunderstanding of Detroit’s experience. He said the pension portion of that grand bargain included new funds from outside sources, cuts in pension benefits, and a “long-term bet” on the city’s capacity to recover, reducing its pension contributions for 10 years while it focused on economic recovery. He calls the model “uncertain.”“The Grand Bargain was a way out of bankruptcy. It wasn’t a grand solution to the pension problem,” he told Bloomberg.Some experts are saying that the initial analyses of the state of Detroit’s pension systems since the approval of the bankruptcy plan in 2014 aren’t encouraging: “The problem is the hole is getting bigger,” said one.The John D. and Catherine T. MacArthur Foundation also dismissed the Manhattan Institute’s call for philanthropic organizations to play a role in resolving Chicago’s $20 billion pension crisis, saying, “A long-term solution to the fiscal challenges in Chicago will require significant political compromise and legislative action that demonstrably are not possible in the context of the current intransigent stalemate in our state capital.”—Martin Levine and Larry KaplanShare5TweetShare1Email6 Shares