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Genetic Findings Lead to New Mouse Model of Autism

Mice carrying a mutation in a gene linked to autism display
January 31, 2010

In the most recent wave of autism genetic studies, the gene neurexin-1alpha has been linked to ASD perhaps more often than any other, drawing attention to our need to better understand how its biological function relates to ASD. Motivated by these genetic findings, in 2009 researchers completed the first detailed behavioral characterization of mice lacking the neurexin-1alpha gene, discovering analogies to at least one core domain of ASD.

Over the past few years, researchers studying ASD from a variety of angles have honed in on what appears to be a central role for proper synaptic functioning in the biology of ASD. Synapses are the specialized sites of nerve cell communication within the brain. Importantly, it is believed that the ability of synapses to regularly change their communication properties is what underlies learning and memory and other forms of neuroplasticity. Scientists have discovered that several genes responsible for producing molecules that are active at synapses are altered in individuals with ASD [see 2008 Autism as a Synaptic Disorder and this year's Study of Genetic Copy Number Variations]. The first synapse genes linked to ASD were the "neuroligins," and much effort has since been directed toward understanding their biological function. Furthermore, in the last two years, no less than eight genetic studies have – incredibly – also implicated abnormalities in a gene, neurexin-1alpha, that produces binding partners of the neuroligin proteins. Neurexin proteins work in tandem with the neuroligin proteins to govern proper operation of synapses. This provides independent support for the role of synaptic function in ASD, and it also makes researchers fairly confident that understanding the complicated biological role of the neuroligin-neurexin signaling pathway will provide important insight into brain function in ASD. However, whereas the biological characterization of animal models lacking neuroligins has been in progress, characterizing the behavioral result of losing neurexin function had not yet been examined.

Researchers from Stanford University and UT Southwestern Medical Center, Dallas have now studied mice lacking neurexin-1alpha, looking for signs of any ASD-related symptoms1. First, they focused on the synapse, and confirmed subtle disruptions in neurotransmission between brain cells. The result of these disruptions was to shift the ratio of excitatory:inhibitory neurotransmission in the brain. This type of change in neural circuitry would indeed be expected to impact brain function and cognition. Next, looking more globally at the behaviors of the mice, they found that although at first pass they appear largely typical, the mice actually had a nearly two-fold increase in stereotyped grooming behaviors (considered a mouse version of human repetitive behaviors), linking the gene to at least one core behavioral feature of ASD. Finally, in a somewhat unexpected result, the researchers tested the animals in several different situations, but found no deficits in social behaviors or anxiety. Fascinatingly, this result contrasts with their earlier work in mice with a specific neuroligin mutation [see 2007 First 'Humanized' Mouse Model], which showed abnormalities in social behavior but no changes in repetitive behaviors. This could mean that the neurexin-1alpha gene plays a unique role in stereotyped behaviors. Alternatively, the currently generated neurexin-1alpha mouse mutant may not fully mimic the human ASD mutation. All of these are possibilities that future research will now be in position to address.

Many animal models exist of the genetic disorders that share overlap with ASD (such as Fragile X, Tuberous Sclerosis etc.) and these models have been responsible for some of the most exciting results to emerge in recent years regarding the treatment of neurodevelopmental disorders [see 2008 Translational Research Places the Spotlight on Treatment of Neurodevelopmental Disorders]. Yet, the creation of model systems of so-called 'idiopathic' autism, autism that is not related to another known medical disorder, is still in the beginning stages, so the characterization of each novel model adds a significant new tool for the research community. Because the animals display some unusual characteristics that are conceptually similar to individuals with ASD, lessons from such mice stand to improve our ability to understand and treat ASD in humans. They also demonstrate that ASD can be dissociated into individual 'phenotypes' which may be independently modeled and studied. In this way, characterization of mouse models with mutations in genes for neuroligins and neurexins, both of which regulate synapses in the brain, highlights how genetic findings can be successfully and immediately leveraged into new autism research opportunities.

1. Etherton et al. Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17998-8003. Epub 2009 Oct 12. [PubMed link: 19822762]