Highlights from IMFAR 2008:
Friday, May 16
A Genetically Accurate Mouse Model of Autism: Disease-linked Point Mutation in Neuroligin-3 Produces Autism-like Behavior in Mice
K. Tabuchi
Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390
J. Blundell
Neurology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390
M. R. Etherton
Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390
R. Hammer
Biochemistry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390
X. Liu
T. Sudhof
Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390
C. M. Powell
Neurology and Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8813
Abstract
Background: A small percentage of patients with autism spectrum disorders carry missense or nonsense mutations in genes encoding neuroligin-3 and -4, which are postsynaptic cell adhesion molecules. One of these mutations, the R451C substitution in neuroligin-3, alters a conserved residue in the extracellular esterase-homology domain of neuroligin-3 in patients with autism or Asperger Syndrome. In addition, mutations in the neuroligin binding partners, neurexin-1 and shank-3, have also found in patients with ASDs. Thus, mutations in three gene families that encode neuroligins or their interacting proteins are associated with familial ASDs.
Objectives: To create and characterize a genetically accurate mouse model of autism.
Methods: We have introduced the R451C-substitution in neuroligin-3 into mice by homologous recombination. All experiments were performed blind to genotype on 19 male neuroligin-3 R451C knockin mice and 19 wild-type, littermate controls. A thorough array of behavioral tests relevant to autism and cognitive function, whole cell synaptic electrophysiology, electron microscopy, Western blot for synaptic proteins, and immunohistochemistry for synaptic proteins were performed.
Results: R451C-mutant knockin mice showed selective impairment in social interaction while other behavioral domains including anxiety, locomotor activity, coordination, and pain sensitivity were spared. Interestingly, the mutants exhibited a significant enhancement in spatial learning abilities in the Morris water maze.
Unexpectedly, these behavioral changes were accompanied by an increase in inhibitory synaptic transmission in the cortex, with no apparent effect on excitatory synapses. Deletion of neuroligin-3, in contrast, did not cause such changes, indicating that the R451C-substitution likely represents a gain-of-function mutation.
Conclusions: The neuroligin-3 R451C knockin mice may represent the first genetically accurate model of autism not associated with a broader neuropsychiatric syndrome. Furthermore, in agreement with recent findings of decreased cortical excitability in mouse models of Rett syndrome, increased inhibitory synaptic transmission may contribute to human ASDs (Tabuchi et al, Science, 2007).
Lay Abstract
Mice containing a mutated human gene implicated in autism exhibit the poor social skills of the disorder, but also show increased ability in one test of specialized cognitive ability, researchers at UT Southwestern Medical Center have found.
The researchers' study also shows how the mutation affects nerve function and provides an animal model that might allow further study of the debilitating condition.
A small percentage of autism cases are genetically linked, and have been associated with mutations that affect molecules called neuroligins, which link nerve cells together, or with molecules that the neuroligins latch on to.
The researchers genetically engineered mice to carry the same mutation in one type of neuroligins, called neuroligins-3, that occurs in some human cases of autism.
These mice showed abnormal social interaction with other mice, just as humans with autism have difficulty relating to other people. The mice did not show problems with anxiety, coordination, or pain sensitivity. They did, however, show an increased ability to solve a swimming maze.
These "knock-in" mice containing the mutated gene may represent the first genetically accurate model of autism that is not confounded by additional neurological disorders, the researchers concluded.
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