Marlene Busko
May 28, 2008 (London, United Kingdom) — Mice containing a mutation in a gene encoding neuroligin-3, which is implicated in human autism, may represent the first genetically accurate model of autism that is not confounded by other neurological diseases, researchers report.
The study, by Craig M. Powell, MD, and colleagues, from the University of Texas Southwestern Medical Center, in Dallas, Texas, showed that mice with a neuroligin-3
R451C substitution exhibited impaired social interaction but also showed superior spacial learning skills.
Dr. Powell presented these findings in an oral presentation at the 7th Annual International Meeting for Autism Research. Part of this work was recently published (Tabuchi K et al. Science. 2007;318:71-76).
"We've created the first animal model that’s a genetically accurate model of autism that’s not associated with other neuropsychiatric syndromes like fragile X syndrome, Rett's syndrome, or tuberous sclerosis," Dr. Powell told Medscape Psychiatry.
Their data suggest that this mouse model may be useful to better understand the molecular mechanism of autism and ultimately to design and test new therapeutic approaches, he added.
What Is Happening in the Autistic Brain?
During the past several years, scientists have been attempting to develop an appropriate animal model for autism, the group writes.
A small percentage of patients with autism spectrum disorder (ASD) carry mutations in genes encoding neuroligin-3 and -4, which are postsynaptic cell-adhesion molecules, they note. In addition, mutations in neuroligin binding partners, neurexin-1 and shank-3, have also been found in patients with ASD.
The team aimed to create and characterize a genetically accurate mouse model of autism by introducing a mutation linked with autism — the R451C substitution in neuroligin-3 — into mice.
The researchers examined the performance of 19 "knock-in" mice with this mutation vs 19 wild-type littermate controls in a variety of behavioral tests relevant to autism. They also performed various tests to measure synaptic protein activity.
Compared with the control mice, the R451C-mutant knock-in mice showed impaired social interaction, but they had normal anxiety, coordination, and sensitivity to pain. Interestingly, the mice with the mutated gene performed better in the Morris water maze, which showed that they had enhanced spatial learning ability.
Unexpectedly, these behavioral changes in the mutant mice were accompanied by an increase in inhibitory synaptic transmission in the cortex.
Encouraging Early Results
"These are very encouraging preliminary data," said Dr. Powell.
"What we are trying to do now is target the changes in synaptic function in these mice — the increase in inhibitory synaptic function in the cortex," he said. "We're using drugs that might reduce the level of inhibition that's abnormally elevated in the knock-in mice," he added, noting that it is hoped that this will treat the behavioral symptoms in the mice.
By looking at more mouse models and gaining a better understanding of what is wrong with the brain in autism, researchers hope to find common pathways that would some day be potential drug targets for patients, he said.
7th Annual International Meeting for Autism Research: Oral Presentation 132.1. May 15-17, 2008
taken from medscape.com
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