Genetic animal models of Autism

Abstract

Rare genetic mutations linked to autism include synaptic cell adhesion molecules neuroligins and neurexins as well as the signalling molecule PTEN. Mice with autism-associated mutations in neuroligins (Tabuchi et al, Science, 2007; Blundell et al, J. Neuroscience, 2010) and neurexins (Etherton et al, PNAS, 2009) demonstrate behavioral manifestations relevant to autism. Our most recent work demonstrates that neuroligin-1 and neurexin-1 deletion models demonstrate increased repetitive behavior. Electrophysiologic studies suggest decreased excitatory to inhibitory balance as a common theme. In particular, neuroligin- 1 deletion mice have decreased NMDA receptor-mediated neurotransmission. Systemic administration of the NMDA receptor partial co-agonist, D-cycloserine, can actually rescue the increased grooming behavior in this model, suggesting a potential therapeutic target for future studies (Blundell et al, J. Neuroscience, 2010). The PTEN conditional mouse model of autism exhibits macrocephaly, seizures, decreased social interaction, anxiety, and altered neuronal morphology (Kwon et al, Neuron, 2006), all of which are successfully treated using the FDA-approved drug rapamycin (Zhou et al, J. Neuroscience, 2009). These genetic models of idiopathic autism and are leading us to novel drug targets for autism.