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News Brief: Schizophrenia Suspects Neurexin and Shank3 Drawn Closer Together

9 November 2012. A study in the October 23 Journal of Neuroscience reports that Shank3, a postsynaptic protein implicated in schizophrenia and autism, molds signaling across the synapse via neuroligin and neurexin, two other molecules that have garnered attention from schizophrenia and autism researchers. Led by Craig Garner of Stanford University in Palo Alto, California, the study probes the interactions between these molecules in cultured neurons from the rat hippocampus, and provides evidence for their convergent function.

Making and maintaining a synapse means assembling and aligning the molecular machinery on the sending and receiving sides of the synapse. The neurexin-neuroligin complex plays a leading role in this: when neurexin, poking out of the presynaptic axon, binds to a postsynaptically located neuroligin, it triggers changes on both sides, including recruitment of neurotransmitter-containing vesicles on the presynaptic side and clustering of receptors to receive these chemical signals on the postsynaptic side (see SRF related news story). The new study finds that Shank3, a postsynaptic scaffolding protein with a binding site for neuroligins, works through this complex. Overexpression of Shank3 increased clustering of presynaptic vesicle markers and postsynaptic density markers, but blocking the interaction between neurexin and neuroligin selectively prevented the presynaptic changes induced by Shank3. This points to the neurexin-neuroligin bridge across the synapse as being a key transducer of instructions from one side to the other.

The findings offer some cohesion to the diverse genes turning up in brain disorders. Genetic studies find mutations affecting neurexin in autism, schizophrenia (see SRF related news story), and other mental illnesses; neuroligin in autism; and Shank3 in both autism (Durand et al., 2007) and schizophrenia (see SRF related news story). When the researchers tested Shank3 proteins mimicking the missense mutations found in autism, recruitment of both presynaptic and postsynaptic molecules was compromised, decreasing the resulting glutamatergic signals. There are probably other molecules within the complicated synaptic machine that can modulate this trans-synaptic signaling, something emphasized by the new discovery that γ-secretase, a much studied enzyme in Alzheimer’s disease, cleaves neuroligin 1 (see SRF related news story). Together, the findings suggest there are different ways to “break” a synapse, and how that happens may help determine the disorder.—Michele Solis.

Reference:
Arons MH, Thynne CJ, Grabrucker AM, Li D, Schoen M, Cheyne JE, Boeckers TM, Montgomery JM,Garner CC. Autism-Associated Mutations in ProSAP2/Shank3 Impair Synaptic Transmission and Neurexin-Neuroligin-Mediated Transsynaptic Signaling. J Neurosci. 2012 Oct 24;32(43):14966-78. Abstract

 
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