Sudhof presented an intriguing study that asks whether mutations in two key cell adhesion proteins, the neuroligins and the neurexins, may alter synapse function and thereby play a role in autism spectrum disorders.
The neurexins and the neuroligins, which lie at the presynapse and the postsynapse respectively, bind to each other thus bridging the synapse. Neurexin interacts with CASK, a protein important for defining structural aspects of the nerve terminal, and a host of other proteins to create a scaffolding complex at that site. Neuroligins on the other hand, bind PSD-95 at the postsynaptic cleft, creating its own scaffolding complex.
It has been shown that neuroligins play a role in the formation of synapses and are important determinants of presynaptic differentiation.
Based upon mutations in neuroligin seen in patients who present with an autism spectrum disorder, Sudhof's group chose to knock-in a R451C mutation into neuroligin-3; a knock-out animal model of neuroligin 3 did not did not have any major effect on phenotype.
The group found that the knock-in mice had impaired social interactions. This was assessed via the animal's interaction with an inanimate object versus a social object (such as another mouse). They also found that these animals exhibited an enhancement in spatial learning, a behavorial aspect studied with the Morris water maze.
Electrophysiological data demonstrated that knocking in this mutation to neuroligin-3 led to an increase in inhibitory mini (mIPSCs) frequency in somatosensory cortex. This is a finding that may correspond to the impaired social interaction phenotype, as people who have autism exhibit inappropriate reactions to social stimuli. Perhaps there is not enough activity taking place in this area. The researchers also unexpectedly found that excitatory neurotransmission (EPSCs) in the hippocampus are increased, potentially causing the displayed enhancement in learning and memory tasks.
In the future, Sudhof and a team of other scientists hope to expand their search for other candidate genes that are important in the autism spectrum disorders using gene arrays.
It's interesting to note that the study of neurexins and neuroligins began with use of alpha-latrotoxin from the black widow spider. It was found that this toxin binds to neurexin, causing an increase in neurotransmitter release. Curious as to the identity of neurexin's endogenous ligand, further experiments yielded to that being neuroligin.