Molecular Pathogenesis of Autism: A Role for Neurexin and Neuroligin




Etherton, Mark Richard

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The Autism Spectrum Disorders (ASDs) represent a clinically heterogeneous group of diseases that share deficits in three core domains: social interaction, communication, and repetitive behaviors and/or restricted interests. The strong genetic basis of these disorders, which was demonstrated by multiple twin and family studies, has prompted the search for candidate genes. Neurexin and neuroligin, trans-synaptic ligands for each other, are two families of synaptic cell-adhesion molecules that have been linked to ASD pathogenesis. I found that three different mouse models for ASDs, the neurexin-1α deletion, the neuroligin-3 (NL3) R451C mutation, and the NL3 R704C mutation all aberrantly alter synaptic transmission. First, I showed that deletion of neurexin-1α in a mouse, which induced behavioral abnormalities consistent with increased repetitive behaviors, significantly reduced AMPA-receptor mediated synaptic transmission in the hippocampus. Next, I demonstrated that the NL3 R451C mutation, which has impaired social interaction, has circuit-specific abnormalities in synaptic transmission. In the somatosensory cortex, inhibitory transmission is enhanced, while in the hippocampus, excitatory transmission is increased. I went on to demonstrate that in the hippocampus, the NL3 R451C mutation appears to deleteriously impair synapse morphogenesis. Lastly, I found that the NL3 R704C mouse model also had a significant reduction in AMPA-receptor mediated transmission in the hippocampus. Taken together, these findings suggest several points. First, each of these mouse models has abnormalities in synaptic transmission, indicative of a synaptic pathology to ASD. Secondly, each of the dysfunctions in synaptic transmission are different, suggesting that comparable to the disease presentation, the pathology may also be heterogeneous. Lastly, for one mouse model, the NL3 R451C, the synaptic deficits were circuit specific, highlighting the observation that ASDs may be an manifestation of variable dysfunctions in multiple brain regions.

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