These are immediate reactions from parents of children living with autism spectrum disorders when I begin to explain our research. They are very valid, insightful, and important questions.
My laboratory at the University of Texas Southwestern Medical Center in Dallas, Texas, in collaboration with Luis Parada, Ph.D. at UT Southwestern and Thomas Südhof, M.D. at Stanford University, studies genetic mouse models of autism. Our primary goal is to identify how autism-linked genetic differences alter brain function, and how that in turn leads to atypical behaviors relevant to autism spectrum disorders (ASD). Once we understand the brain function differences that result from a genetic mutation, we then correct the functional problem with drugs and test the drug’s ability to reverse or “treat” the behavioral differences in the genetic mouse model of ASD.
Alterations or mutations in certain genes are known to be one cause of ASD. This means that the genetic alteration leads to behavioral differences in people with autism. This is relatively straightforward to study in humans. It is much more difficult to study what is different about brain function in children and adults with ASD.
Because mice have most of the same genes as humans, we are able to re-create in a mouse model the human genetic difference that causes some cases of ASD. The goal is not to create an autistic mouse per se, but rather to determine how the mutation leads to ASD-relevant behavioral differences in the mouse. If we simply create the autism genetic mutation in a mouse and demonstrate that the mouse has decreased social interaction or repetitive behaviors or other behavioral differences, that tells us that the mutation leads to behavioral differences. Of course, we already know that the genetic mutation causes behavioral differences in humans, so that doesn’t get us very far alone. We must then ask how the genetic mutation alters brain function, something we cannot study easily in humans. To do this, we measure neuron activity in the brains of the mice. This tells us precisely how brain function is altered by the genetic mutation. Knowing this allows us to use drugs to revert brain function back to typical function. Once these drugs are identified, we then examine the drug’s effect on the atypical behaviors in the very same mouse model to determine if the drug can revert the atypical behavior to more typical behavior. Reverting atypical behaviors into more typical behaviors is an important goal for many patients with autism and their families.
Some examples:
Our recent publication on Feb. 10, 2010 in the Journal of Neuroscience (http://www.utsouthwestern.edu/utsw/cda/dept353744/files/577306.html or http://www.ncbi.nlm.nih.gov/pubmed/20147539?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1 ) examined mice with a deletion of the autism-linked gene neuroligin-1. These mice show repetitive behaviors, one of the core diagnostic features of autism, and learning problems, a feature sometimes associated with ASD. By examining the synaptic connections between neurons in the brains of these mice, we determined that neuronal communication at synapses involving the neurotransmitter glutamate is reduced in this model. Glutamate is the primary excitatory neurotransmitter in the brain. A drug, D-cycloserine, that enhances communication at glutamate-sensitive synapses reduced the obsessive behavior in the animals, suggesting a potential way to treat repetitive behaviors in humans. D-cylcoserine has already been used in a small pilot study in autism patients with suggestion of beneficial effects (), though further studies are warranted. We are now beginning to test other drugs under development at pharmaceutical companies that may affect this same aspect of brain function and may also treat these atypical repetitive behaviors.
In an interesting twist, similar repetitive behavioral differences were also observed in neurexin-1a mutant mice, a study published in Oct. 2009 that was identified by Autism Speaks as one of the Top Ten Research Achievements of 2009. We are now beginning to examine the specific alterations in brain function in the neurexin model and to determine if the same drugs are effective at reducing obsessive, repetitive behaviors in this model. Our hope is that by examining multiple genetic models of autism, we can find a common difference in brain function that will lead to more general treatments for patients with autism who desire such treatment. At the very least, the drugs we identify are important candidates for treating those patients with the specific genetic cause of autism under study.
We are also continuing to study a genetic model based on mutations in the neuroligin 3 gene. These mice do not have repetitive behaviors, but instead exhibit mild social interaction differences. This study was published in the journal Science in 2007 and was also identified by Autism Speaks as one of the Top 10 Autism Research Achievements of that year. Along with the laboratory of our collaborator, Dr. Südhof at Stanford, we are examining several important aspects of brain function in this model including how other genes may interact with the mutation to alter the behavioral differences, how the mutation leads to abnormal brain function, and how we might begin to treat this abnormal brain function.
Last, but not least, in close collaboration with Dr. Parada here at UT Southwestern, we have characterized a genetic model based on brain-specific deletion of the PTEN gene, a gene associated with autism in children with brain overgrowth or “macrocephaly”. Again, this publication in the journal Neuron was among a group of findings identified by Autism Speaks as a Top 10 Autism Research Event. This initial publication established this mutant mouse as a model for autism with social interaction differences, anxiety, frequent seizures, and abnormally large heads, brains, and nerve cells. Through our understanding of the brain molecules altered by this genetic mutation, we have since successfully used an FDA-approved drug to “treat” the behavioral differences, the seizures, and the brain and nerve cell structural changes. This finding was published in the Journal of Neuroscience in Feb. 2009. This drug is now being tested by other researchers in patients with Tuberous Sclerosis, a genetic disorder with an unusually high incidence of ASD.
What does the future hold for genetic autism model research? As human geneticists identify additional genes responsible for some cases of autism, we must continue to study how these mutations alter brain function in animal models. By understanding the relationship between the mutations and altered brain function, something we can only test using animal models, additional treatment targets can be identified to help children and families with autism who are interested in this approach.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our eighth item, Creation of Neuroligin-3 Mutant Mouse, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
