Autism Spectrum Disorders: Tales from the Mouse

On Friday, January 24, I attended "Autism Spectrum Disorders: Tales from the Mouse," Dr. “Manny” DiCicco-Bloom’s keynote presentation to the Neuroscience, Behavior and Health Research Forum offered by the Vermont Chapter of the Society for Neuroscience. As a clinician I hoped to learn more about Autism Spectrum Disorders (ASD), as a researcher-in-training I wanted to hear about mouse models, and as a translational science student I wanted to get ideas for presenting research on a clinical condition to a mixed audience.

You will find some detailed notes on content below, but here is my take-away list:

1. “Everybody who has autism has a different type of autism” so there’s no hope of finding a single common cause or single effective treatment. Researchers have to make each kind of model and look for the pathways that can be fixed. [This is directly analogous to my work in Auditory Processing Dysfunction.]
2. Mouse models allow researchers to identify specific molecular pathway abnormalities that may underlie specific disease symptoms, determine whether altering pathway activities can overcome specific abnormalities, and develop new therapies for human conditions.
3. There is increasing support for an integrated neurobiological approach to studying complex conditions like autism. NIMH launched Research Domain Criteria project (RDoC) to define basic dimensions of functioning that can be studied across domains (genes, neural circuits, behaviors).
4. TimRoberts at CHOP is doing mouse research on auditory pathways in autism!
5. Interactions among researchers, clinicians, government funding agencies, private funding organizations, families, and patients are important, interesting, and complex.

Here are some content notes:

Nationwide prevalence of Autism Spectrum Disorders (ASD) is approximately 1:88 nationwide, similar to mental retardation and cerebral palsy. After acknowledging the challenge of talking about ASD as the DSM-(diagnostic and statistical manual) 4R gives way to new criteria in the DSM-5, Dr. DiCicco-Bloom shared clinical features of autism (social interactions, communications, restricted repetitive behaviors and interests), different historical labels on the spectrum (Autism, Aspergers, pervasive developmental disorder not otherwise specified), and associated conditions (mental retardation, seizures, problem behaviors, anxiety/mood disorders). Children who later develop autism may have detectable developmental differences in motor skills at 6-12 months and eye gaze as early as two months. It’s not always clear who is best to see and treat these patients.

The challenge for basic scientists presented by Dr. DiCicco-Bloom is that the clinical construct of Autism is based on a menu behavior descriptions that don't directly map to specific underlying causes that likely vary among children. How does one go about making a model of a construct that does not have a single definition? “So researchers talk about the nervous system, or the gut, or whatever” they can model. As such, basic scientists are never working on a “mouse model of Autism,” but rather they’re working on a feature of Autism that they can model.

After a brief reorientation to brain anatomy and physiology, Dr. DiCicco-Bloom talked about some developmental brain abnormalities that are seen in children with in autism although they are not absolute features and cannot be used for diagnosis. He outlined different ways genes can be associated with risk (single genes, common variants, copy-number variants) in a way that was exceptionally clear and helpful for me. He shared examples of environmental factors increasing the brain’s vulnerability to damage including peripheral immune system activation (e.g., Sydenham’s chorea, maternal Lupus, schizophrenia) and environmental toxins (e.g., lead, mercury). He mentioned fMRI research that was done partly for the "translational" component of having a familiar clinical measure to discuss with clinicians. Finally, he shared the example of Fragile X syndrome (FXS, the most common inherited form of autism and caused by the silencing of a single gene) as a success story in which a mouse model enabled the discovery of a pharmacological treatment effective to repair neurological and behavioral symptoms in human adults with dendritic spine defect.