View Full Version : Integrative Functional Genomics Implicates Specific Molec. Paths & Circuits in Autism


Amtram
12-15-13, 05:28 PM
I always enjoy reading Emily's posts over at "Science Over A Cuppa," because she makes me think - she introduces concepts and vocabulary I haven't yet encountered and I have to go looking up information. Even so, she explains the science that's being discussed around these things in such a way that I don't always have to, I just want to.

In this particular article (http://scienceoveracuppa.com/2013/12/01/thoughts-on-the-recent-parikshak-et-al-study-integrative-functional-genomic-analyses-implicate-specific-molecular-pathways-and-circuits-in-autism/), she's discussing the article with the title above, and trying to weigh the pros and cons of the findings - what looks promising because it's different, and what seems like nothing unexpected. She starts with a description of the experiment:

To kinda summarize what they did, they took samples of nonautistic human and primate neocortex spanning from ages 8 weeks post-conception to 12 months after birth, studied the relationship between gene expression levels, and were finally able to group a portion of these genes together into 17 separate modules or groups, each of which showed similar patterns of expression in similar areas of brain.

What they found was that modules expressed during earlier neurogenesis (M2 and M3), usually involving some aspect of transcriptional regulation, shared an inverse relationship with those modules (M13, M16, and M17) which were expressed later and are involved with processes like synaptogenesis. So, as expression levels of genes in M2 and M3 went down, M13, M16, and M17 went up. This of course makes some intuitive sense since neurogenesis precedes synaptogenesis.

As the article goes on, she explains that in some portions of the brain, there's more neurogenesis than synaptogenesis, and vice versa, and that genes that play a part in one are not necessarily absent in driving the other. That's kind of something I'd like to explore further at some point, along with the information she brought up about the different cortical layers having different synaptic enrichment. . .something that once I read it seemed like it would be obvious, but which I'd never considered.

Most of what fascinates me about the brain is the functions of different parts - but this kind of research is getting into parts of parts - and pieces of those parts of parts. And it's often easy to forget that the cortex isn't just a single part, too.

Anyway, I thought this would be interesting. I wasn't overwhelmed with excitement over the study making the rounds this week about imaging that shows hyperconnectivity in autism, but this kind of shows that there may be something to it that's more testable and verifiable than imaging alone.

Amtram
12-15-13, 05:48 PM
Ooops, that got truncated pretty badly. Full Title was Integrative Functional Genomic Analyses Implicate Specific Molecular Pathways and Circuits in Autism.

Still looking at SOAC, I see that Emily also connected with a scientist doing research on a mouse model of OCD whose work also ties in with some of the synaptic development studies being done on autism (hence her interest in sharing it.) It's titled "Remembering the Synapse in Autism" (http://scienceoveracuppa.com/2013/11/24/shank3-remembering-the-synapse-in-autism/), and the researcher in question is Guoping Feng (http://sfari.org/news-and-opinion/investigator-profiles/2010/guoping-feng-unearthing-the-roots-of-compulsive-behavior).

This invariably led to his interest in autism. With his background in molecular genetics, he has focused on the SHANK3 pathway, including SAPAP3, a molecule which binds to and interacts with the SHANK proteins. Both the SHANK2 and SHANK3 genes have strong ties with autism, not only as strong candidate genes in terms of mutations, but also research reported just this month has shown that approximately ~15% of autistic brains in their study sample exhibited hypermethylation of the SHANK3 gene.

Much of this work supports the embryonic development model of several psychiatric conditions (meaning that they are neurological and present at birth, not caused by a later emotional or behavioral influence.) She makes sure to point out that these models show that the cause is biological, but have not isolated specific individual mechanisms - it's something structural, but we haven't learned enough yet to say which of the many structures is primary in causing the conditions.

Amtram
12-15-13, 05:52 PM
Oh, and the link on Dr. Feng is interesting too. Partly because his work is one of those occasions in which a researcher was looking for one thing and it led him to something entirely different:

Many projects in Feng's lab focus on the role of scaffolding proteins that assemble near a synapse. A couple of years ago, studying one family of these proteins called SAPAPs inadvertently led him to psychiatric disease.

Feng had planned to create mice carrying specific mutations in SAPAP genes, to see whether and how various synaptic changes affect the animals' behavior. Anticipating subtle differences, he formed a large collaboration with scientists who specialize in measuring mouse behaviors. As it turned out, for the mutants lacking SAPAP3, he didn't need any help from the experts.

"The behavior was so obvious they're basically grooming their skin off. It's very gross," Feng says. The mice are the first robust animal models of compulsive behavior.