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Kids with autism found to have extra connections in brain

Aug. 22, 2014
Courtesy of CUMC
and World Science staff

A study has found that young peo­ple with au­tism have ex­tra syn­apses, or con­nec­tions among cells, in the brain.

That, the in­ves­ti­ga­tors say, is due to a slow­down in a nor­mal pro­cess of “prun­ing” syn­apses that oc­curs dur­ing de­vel­op­ment, which can have pro­found ef­fects be­cause syn­apses are the points where neu­rons, or nerve cells, con­nect and com­mu­ni­cate.

Neu­rons, or branch­ing nerve cells, from au­tis­tic (left) and non-au­tis­tic (right) brains. The "spines" on the neu­rons in­di­cate the lo­ca­tion of synapses. (Cred­it: Guo­mei Tang and Mark S. Son­ders, CUMC)


The re­search­ers, at Co­lum­bia Uni­vers­ity Med­i­cal Cen­ter in New York, al­so found that a drug that re­stores nor­mal prun­ing can re­duce au­tis­tic-like be­hav­iors in mice, even when giv­en af­ter these have ap­peared. This could lead to a “much-needed ther­a­peu­tic strat­e­gy for au­tism,” said Jef­frey Lieber­man, chair of psy­chi­a­try at the cen­ter and di­rec­tor of New York State Psy­chi­at­ric In­sti­tute, who was not in­volved in the stu­dy.

Al­though the drug, ra­pa­my­cin, has side ef­fects that may pre­clude its use in peo­ple with au­tism, “the fact that we can see changes in be­hav­ior sug­gests that au­tism may still be treat­able af­ter a child is di­ag­nosed, if we can find a bet­ter drug,” said the stu­dy’s sen­ior in­ves­ti­ga­tor, neu­ro­sci­ent­ist Da­vid Sul­zer.

The study was pub­lished in the Au­gust 21 on­line is­sue of the jour­nal Neu­ron. Au­tism is a brain condition in­volv­ing de­fi­cits in so­cial in­ter­ac­tion and speak­ing; ina­bil­i­ty to treat oth­ers as peo­ple or make friends; un­u­su­al, re­pet­i­tive be­hav­iors; and some­times ex­traor­di­nary skills in spe­cif­ic ar­eas.

Dur­ing nor­mal de­vel­op­ment, a burst of syn­apse forma­t­ion oc­curs in in­fan­cy, epse­cially in the cor­tex, a brain re­gion in­volved in au­tis­tic be­hav­iors. Prun­ing elim­i­nates about half of these “cor­ti­cal syn­apses” by late ad­o­les­cence. Many au­tism-linked genes af­fect syn­apses. Some re­search­ers had hy­poth­e­sized that au­tis­tic peo­ple may have more of them.

To test this, co-author Guo­mei Tang ex­am­ined brains from young peo­ple with au­tism who had died from oth­er causes. Thir­teen brains came from chil­dren ages two to nine, and 13 brains came from chil­dren ages 13 to 20. Twen­ty-two brains from chil­dren with­out au­tism were al­so ex­am­ined for com­par­i­son.

Tang meas­ured syn­apse con­centra­t­ions in a small part of each brain by count­ing the num­ber of ti­ny spines that branch from these cor­ti­cal neu­rons; each spine con­nects with anoth­er neu­ron via a syn­apse. By late child­hood, she found, spine con­centra­t­ions had dropped by about half in the un­af­fected chil­dren’s brains, but by only 16 per­cent in the brains from au­tism pa­tients.

Clues to what caused the prun­ing de­fect al­so turned up, the sci­ent­ists said. The au­tis­tic chil­dren’s brain cells were filled with old and dam­aged parts and were de­fi­cient in the me­chan­isms behind a mole­cular pro­cess that gets rid of these old com­po­nents. That process is called au­to­phagy, from the Greek for “self-eating.”

Us­ing mouse mod­els of au­tism, the re­search­ers traced the prun­ing de­fect to a pro­tein called mTOR. When mTOR is over­ac­tive, they found, brain cells lose much of their “self-eating” abil­ity. And with­out this abil­ity, the brains of the mice were pruned poorly and con­tained ex­cess syn­apses. “While peo­ple usu­ally think of learn­ing as re­quir­ing forma­t­ion of new syn­apses,” Sul­zer said, “the re­mov­al of in­ap­pro­pri­ate syn­apses may be just as im­por­tant.”

The re­search­ers said they could re­store nor­mal au­to­phagy and prun­ing—and re­verse au­tis­tic-like be­hav­iors in the mice—by giv­ing ra­pa­my­cin, a drug that in­hibits mTOR. That was ef­fec­tive even when giv­en even af­ter the mice had de­vel­oped the be­hav­iors.

Be­cause large amounts of over­ac­tive mTOR were al­so found in al­most all of the brains of the au­tism pa­tients, the re­search­ers spec­u­late that same pro­cesses may oc­cur in chil­dren with au­tism. 

“What’s re­mark­able,” said Sul­zer, “is that hun­dreds of genes have been linked to au­tism, but al­most all of our hu­man sub­jects had over­ac­tive mTOR and de­creased au­to­phagy, and all ap­pear to have a lack of nor­mal syn­ap­tic prun­ing. This said that many, per­haps the ma­jor­ity, of genes may con­verge on­to this mTOR/au­tophagy path­way, the same way that many trib­u­tar­ies all lead in­to the Mis­sis­sip­pi Riv­er.”


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A study has found that young people with autism have extra synapses, or connections among cells, in the brain. That, the investigators say, is due to a slowdown in a normal process of “pruning” synapses that occurs during development, which can have profound effects because synapses are the points where neurons, or nerve cells, connect and communicate. The researchers, at Columbia University Medical Center in New York, also found that a drug that restores normal pruning can reduce autistic-like behaviors in mice, even when given after these have appeared. This could lead to a “much-needed therapeutic strategy for autism,” said Jeffrey Lieberman, chair of psychiatry at the center and director of New York State Psychiatric Institute, who was not involved in the study. Although the drug, rapamycin, has side effects that may preclude its use in people with autism, “the fact that we can see changes in behavior suggests that autism may still be treatable after a child is diagnosed, if we can find a better drug,” said the study’s senior investigator, neuroscientist David Sulzer. The study was published in the August 21 online issue of the journal Neuron. During normal development, a burst of synapse formation occurs in infancy, epsecially in the cortex, a brain region involved in autistic behaviors. Pruning eliminates about half of these “cortical synapses” by late adolescence. Many autism-linked genes affect synapses. Some researchers had hypothesized that autistic people may have more of them. To test this, co-author Guomei Tang examined brains from children with autism who had died from other causes. Thirteen brains came from children ages two to nine, and 13 brains came from children ages 13 to 20. Twenty-two brains from children without autism were also examined for comparison. Tang measured synapse concentrations in a small part of each brain by counting the number of tiny spines that branch from these cortical neurons; each spine connects with another neuron via a synapse. By late childhood, she found, spine concentrations had dropped by about half in the unaffected children’s brains, but by only 16 percent in the brains from autism patients. Clues to what caused the pruning defect also turned up, the scientists said. The autistic children’s brain cells were filled with old and damaged parts and were very deficient in a chemical process that gets rid of these old components, called “autophagy.” The word comes from the Greek for “self-eating.” Using mouse models of autism, the researchers traced the pruning defect to a protein called mTOR. When mTOR is overactive, they found, brain cells lose much of their “self-eating” ability. And without this ability, the brains of the mice were pruned poorly and contained excess synapses. “While people usually think of learning as requiring formation of new synapses,” Sulzer said, “the removal of inappropriate synapses may be just as important.” The researchers said they could restore normal autophagy and pruning—and reverse autistic-like behaviors in the mice—by giving rapamycin, a drug that inhibits mTOR. That was effective even when given even after the mice had developed the behaviors. Because large amounts of overactive mTOR were also found in almost all of the brains of the autism patients, the researchers speculate that same processes may occur in children with autism. “What’s remarkable,” said Sulzer, “is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning. This said that many, perhaps the majority, of genes may converge onto this mTOR/autophagy pathway, the same way that many tributaries all lead into the Mississippi River.”