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Drug calms overly excitable brains in autism rodent models

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Jessica Wright
10 February 2014

Brain boost: An electrode (arrow) placed in the brain of a rat model of autism shows overactivity in the region that processes memory.

The blood pressure drug bumetanide normalizes a deficit in brain activity in two rodent models of autism, according to a study published last week in Science1. The study hints at a mechanism underlying the drug’s benefits for people with autism.

Neurochlore, a company based in Marseilles, France, is testing bumetanide as a treatment for autism. In the first phase, 27 children with autism showed some improvement in their autism symptoms2; the researchers are continuing the trial in Europe with more participants. (This work is partly funded by the Simons Foundation, SFARI.org’s parent organization.)

People with autism are thought to have an imbalance between excitatory and inhibitory signals in their brain. The resulting overabundance of excitatory signals may explain why about one-third of people with autism also have epilepsy, for example.

In the typical human brain, the chemical messenger gamma-aminobutyric acid (GABA) normally damps down neuronal activity. But in people with autism, one theory holds, GABA functions instead as an excitatory messenger, turning up brain activity and leading to the signal imbalance.

This theory is difficult to test because doing so would require researchers to implant electrodes in human brains. But there is suggestive evidence from a small study that found that the sedative Valium — which enhances GABA activity — makes children with autism more aggressive instead of calming them3. There are also reports that drugs that activate GABA exacerbate epilepsy in some people4.

More generally, several lines of evidence link autism to GABA: Some people with the disorder carry mutations in GABA receptor genes or show differences in neurons that relay inhibitory signals, for example. 

Bumetanide may restore the normal balance of brain signals by switching GABA back to an inhibitory role, according to Yehezkel Ben-Ari, director of the Mediterranean Institute of Neurobiology at INSERM in Paris and founder of Neurochlore.

“Many of my colleagues were skeptical,” says Ben-Ari. “But very often such theoretical things turn out to be right.”

GABA switch:

In 1989, Ben-Ari and his colleagues showed that in rodents, GABA normally activates brain signals before birth5. Between days 8 and 12 after birth, however, the rodents undergo a permanent switch that makes GABA the primary inhibitory molecule in their brain.

In a follow-up study, published in Science in 2006, the researchers found that GABA also temporarily switches from an excitatory to an inhibitory role at birth and switches back about two days after birth6. Blocking oxytocin, a hormone that rushes through the mother’s system during labor, prevents this temporary switch from occurring.

The findings suggest that oxytocin mediates the temporary GABA switch, perhaps protecting the brain from the onslaught of hormones that occur during birth, says Ben-Ari.

In the new study, he and his colleagues tested their theory in two rodent models of autism: mice that model fragile X syndrome and rats exposed to the epilepsy drug valproate (VPA) in utero, a well-established environmental model of autism.

They found that in these rodents, GABA is an excitatory messenger both before birth and up to 1 month of age. The researchers did not look at longer time periods, but it is possible that GABA remains excitatory indefinitely, says Ben-Ari. They also found that blocking oxytocin in control rats as they give birth blocks the GABA switch in their pups and triggers some autism symptoms.

Another study, published 8 January in the Journal of Neuroscience, found that fragile X model mice make the GABA switch 15 days after birth compared with about 10 in controls7. The difference in timing observed in the two studies may be because Ben-Ari’s team looked at neurons in the hippocampus whereas this study looked at the cortex, says lead investigator Anis Contractor, associate professor of neurobiology at Northwestern University, in Chicago.

Still, finding the same results in two models of autism, one environmental and one genetic, strengthens Ben-Ari’s study, Contractor says. “It speaks to a common mechanism.” 

Treating pregnant rodents with bumetanide one day prior to their giving birth normalizes the GABA deficits in the pups. It also prevents the pups’ abnormal vocalizations.

“This points to very strong evidence for deficits in GABA inhibition as a causal relationship with autism, ” says Stephen Moss, professor of neuroscience at Tufts University in Medford, Massachusetts. “[This] is consistent with what a lot of people thought but no one had actually proven.”

The results also suggest that treatments for autism are most effective when given early, says Ben-Ari.

“If we want to understand how to treat autism, we have to work from neurodevelopment and identify the earliest networks that are wrongly connected or wrongly operating,” he says.

The most likely mechanistic explanation for bumetanide’s effects is that it triggers the GABA switch by lowering the level of chloride ions, Ben-Ari says. The autism mouse models have low levels of a chloride exporter, which keeps the level of chloride in the cells elevated. Bumetanide might reverse this effect.

“Mechanistically, [the study] points to something that may be really important for autism, but what the actual mechanism is needs to be further understood,” says Moss.   

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Tyzio R. et al. Science 343, 675-679 (2014) Abstract

2: Lemonnier E. et al. Transl. Psychiatry 2, e202 (2012) PubMed

3: Morrosu F. et al. Funct. Neurol. 2, 355-361 (1987) PubMed

4: Nardou R. et al. Brain 134, 987-1002 (2011) PubMed

5: Ben-Ari Y. et al. J. Physiol. 416, 303-325 (1989) PubMed

6: Tyzio R. et al. Science 314, 1788-1792 (2006) PubMed

7: He Q. et al. J. Neurosci. 34, 446-450 (2014) PubMed

Comments

Name: ASD Dad
11 February 2014 - 11:01AM

Interesting work in which I particularly liked this passage

"Still, finding the same results in two models of autism, one environmental and one genetic, strengthens Ben-Ari’s study, Contractor says. “It speaks to a common mechanism.”

Having said that the identification of sub groups / sub types of autism needs some serious work that flows on from the findings by Harvard researchers earlier this year ... http://www.ncbi.nlm.nih.gov/pubmed/24323995 that may aid the refinement and efficacy of such treatment paradigms.

Name: SAM
11 February 2014 - 3:58PM

Autism word is so large. But when it comes to clinical studies they never mention any groups or subgroups. It is kind of trial error test. No biology or mecanism explained behind the rational.

Name: Jessica Wright
11 February 2014 - 4:01PM

Thank you for your comment ASD Dad, we also covered this study for SFARI.org:
https://sfari.org/news-and-opinion/news/2014/electronic-medical-records-may-reveal-subgroups-of-autism

It does show that researchers need numbers in the thousands to divide autism into subgroups. This makes subgroups challenging for preliminary clinical trials, which are typically small.

Name: Sarah
11 February 2014 - 4:16PM

An overactive brain, I think is huge problem for our kids and any drug that can calm the brain provided there are minimal side effects is promising. My son is currently on a beta blocker called Propranolol and it helps a lot. His teacher told me she's seen positive changes in class since he's been taking this medicine (more compliance, less aggression, even more speech). Propranolol has a calming effect on the brain and helps our kids cope with stress. He is taking a low dose 2 ml/ 2 times/ day. So far so good.

Name: Candie
1 April 2014 - 1:40AM

So many studies on autism. So vague. Seems like every study ends with "further research needed" "further studies needed." It's just an endless display of research that is used to generate more funding in the absence of any hope. Never any concrete answers. Sloppy research that doesn't study specific types of autism, for example, why not study autistic adults who have epilepsy? Or autistic children who engage in self injury that targets their nose? Narrow it down for gosh sakes. This broad spectrum approach isn't helping.

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