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Friday, May 16, 2008: 3:45 PM
Avize-Morangis (Novotel London West)
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).
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).