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Office of Autism Research Coordination (OARC) logo

Function and dysfunction of neuroligins  

Autism arises, at least in part, as a result of poor signaling between neurons, which disrupts the behavioral pathways necessary for social interactions, language development and motor control. At Stanford University, Thomas Südhof and his colleagues plan to study how proteins called neuroligins regulate neuronal signaling, in order to understand their role in those behavioral pathways and in autism. Neurons communicate at structures called synapses, specialized signaling centers that regulate and mediate communication between the two cells. Within the synapse, neuroligins on the signal-receiving cell reach across to proteins called neurexins on the signal-sending cell. This interaction strengthens the connection between the two neurons and is necessary for signaling activity. Neuroligins play a key role in maintaining the balance of excitatory and inhibitory signals in the brain so that information is transmitted properly between the neurons of a pathway. The abnormal patterns of brain activity in autism suggest that many neurons are not sending robust signals across the synapse, and several neuroligin genes have been implicated in the disorder through genetic studies. In 2007, Südhof and colleagues reported that mice with autism-associated mutations in one neuroligin gene — neuroligin 3 — show several features of the disorder, including reduced social interactions and repetitive behaviors. Neuroligin 3 is important for both excitatory and inhibitory synapses, whereas neuroligin 1 and neuroligin 2 regulate the activity of only excitatory or only inhibitory synapses, respectively. Finally, the role of neuroligin 4, which is also implicated in autism — is still unknown. Südhof and colleagues plan to study how each of these neuroligins regulates synapse activity in order to understand the proteins' role and that of excitatory and inhibitory signals in the behavioral pathways affected in autism. The researchers plan to make mutations in all neuroligin genes in mice, and then determine whether the mutations affect the balance of signals in neural communication networks. Based on their observations, they hope to deduce the role of excitatory and inhibitory signals in the neurological pathways for social interactions and repetitive behavior. They also plan to uncover the cellular mechanism of neuroligins in synaptic activity to understand how autism-associated mutations disrupt the activity. Through these experiments, Südhof and colleagues aim to uncover the role of neuroligins in establishing and maintaining the signaling steps necessary to process information in the brain. Their findings may indicate ways to therapeutically correct the balance of inhibitory and excitatory signals in the brains of people with autism. To date, the Südhof laboratory has, by a combination of genetic, electrophysiological and biochemical studies, found that the autism-related R451C mutation in the neuroligin 3 gene causes region-specific changes in synaptic strength. In addition, they have observed a new point mutation in neuroligin 4, which inactivates neuroligin-4 function. It appears that different neuroligins perform distinct functions in different synapses. The Südhof laboratory has also generated new mouse models for autism that are now being characterized, with the hope of gaining a better understanding of the link between autism and synaptic function. Project Status


Funder Simons Foundation
Fiscal Year Funding $374,382.79
Current Award Period 2007-2010
Project Number SFARI-07-41
Principal Investigator Sudhof, Thomas
Received ARRA Funding? No
Strategic Plan Question Question 4: Which Treatments And Interventions Will Help? (Treatments)
Subcategory Model Systems/Therapeutic Targets
Strategic Plan Objective Green dot: Objective has greater than or equal to the recommended funding. 4SB. Standardize and validate at least 20 model systems (e.g., cellular and/or animal) that replicate features of ASD and will allow identification of specific molecular targets or neural circuits amenable to existing or new interventions by 2012. IACC Recommended Budget: $75,000,000 over 5 years.
Federal or Private? Private
Institution Stanford University
State/Country California
Web Link 1 Function and dysfunction of neuroligins (External web link)
Web Link 2 No URL available.
Web Link 3 No URL available.
New! History/Related Projects Function and dysfunction of neuroligins | $498,884.68 | 2009 | SFARI-07-41
Function and dysfunction of neuroligins | $498,665.39 | 2008 | Project number unavailable
Function and dysfunction of neuroligins in synaptic circuits | $150,000.00 | 2010 | 177850