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Reversing Autism in Mice
Autism comprises a heterogeneous group of neurodevelopmental disorders characterized by defects in communication and social inter action. A group of nonsyndromic forms of autism is associated with mutations in the neuroligin genes, which encode postsynaptic adhesion molecules. Using a reversible knockout approach, Baudouin et al. (p. 128, published online 13 September) investigated the in vivo functions of neuroligin-3 in the mouse cerebellum. Mutant mice showed a major defect in metabotropic glutamate receptor–dependent, long-term potentiation; disrupted heterosynaptic competition; and ectopic synapse formation in vivo. These synaptic defects could be rescued by reactivation of the neuroligin gene in the adult.
Abstract
The genetic heterogeneity of autism poses a major challenge for identifying mechanism-based treatments. A number of rare mutations are associated with autism, and it is unclear whether these result in common neuronal alterations. Monogenic syndromes, such as fragile X, include autism as one of their multifaceted symptoms and have revealed specific defects in synaptic plasticity. We discovered an unexpected convergence of synaptic pathophysiology in a nonsyndromic form of autism with those in fragile X syndrome. Neuroligin-3 knockout mice (a model for nonsyndromic autism) exhibited disrupted heterosynaptic competition and perturbed metabotropic glutamate receptor–dependent synaptic plasticity, a hallmark of fragile X. These phenotypes could be rescued by reexpression of neuroligin-3 in juvenile mice, highlighting the possibility of reverting neuronal circuit alterations in autism after the completion of development.
