A Children's Hospital Boston study featured on the cover of the July 11 Science implicated a half-dozen new genes in autism. More importantly, it supports the emerging idea that autism stems from disruptions in the brain's ability to form new connections in response to experience—consistent with autisms onset during the first year of life, when many of these connections are normally made.
An interdisciplinary team led by Christopher Walsh, MD, PhD, chief of Genetics, studied 88 large Middle Eastern families with a high incidence of autism and marriages between cousins (increasing the likelihood of rare inherited mutations). To ensure that autism was rigorously diagnosed, Walsh's team trained collaborators in the Middle East to administer standardized assessments.
Eric Morrow, MD, PhD, of Genetics (who shares first authorship of the study with Seung-Yun Yoo, PhD, of Genetics), along with Janice Ware, PhD, and Elaine Leclair, PhD, of the Developmental Medicine Center, flew to Turkey, Dubai, Kuwait and Saudi Arabia to examine the children and confirm the diagnoses. The team then compared the DNA of family members with and without autism, searching for recessive mutations—those causing disease only when a child inherits two copies. In all, they identified five chromosome deletions affecting at least six identifiable genes, one of which was also mutated in some European and American children with autism.
Walsh then compared notes with Michael Greenberg, PhD, director of Children's Neurobiology Program. It turned out that Greenberg's lab had already pegged three of the genes (c3orf58, NHE9, and PCDH10) as players in a complex molecular network that orchestrates the refinement and maturation of brain connections, or synapses, in response to experience. "This network can be disrupted in a myriad of ways," says Greenberg. "Taken together, our findings suggest that experience-dependent learning could be relevant to autism, and that autism might result from the deregulation of any of a number of genes that are part of the same pathway."
Notably, only one chromosome deletion found by Walsh's team actually removed a gene; most often, what was lost was the "on/off" switch. Walsh sees great hope in this finding: Since the gene itself is intact, it may be possible to reactivate it, through medications or behavioral therapies, and ease the effects of autism.
Watch a video of Walsh talking about his research.
Up to 35 percent of babies who survive prematurity are left with brain damage leading to cerebral palsy and cognitive/behavioral deficits. Now, neuroscientist Frances Jensen, MD, with Simon Manning, MD and Delia Talos, MD in the Department of Neurology and the Neurobiology Program, reports that memantine (Namenda), a drug originally developed for Alzheimer's disease, may reduce the damage.
For more than a decade, Jensen and others at Children's have shown that premature newborns rapidly developing brains have unique characteristics that not only heighten their vulnerability to hypoxia-ischemia (a common complication of prematurity that compromises the brains blood and oxygen supply), but also prevent these infants from responding to existing neurologic drugs. But Jensen has been finding new targets unique to the newborn brain—as well as drugs that can hit them, some of them already FDA-approved.
Now, in the June 25 Journal of Neuroscience, Jensen's team shows that preterm infants oligodendrocytes, the cells that form the brains white matter, are especially rich in NMDA receptors, a type of glutamate receptor. After a hypoxic-ischemic insult, glutamate builds up and can over-activate NMDA receptors, producing a pattern of white-matter injury known as periventricular leukomalacia (PVL), the most common cause of cerebral palsy.
However, working with a rat model of PVL, Jensen and colleagues found that giving memantine—which acts by blocking the NMDA receptor—significantly reduced white-matter injury after a hypoxic-ischemic insult. Back in the 1990s, Children's participated in memantines development as a treatment for Alzheimers disease. Now, if Jensen can establish the drugs safety in premature newborns, she wants to test it as a protective therapy.