“Synapse” is a ref-flag word nowadays in many sects of autism research. For Dan Geschwind of UCLA, a highly intelligent and very talented molecular biologist, this is definitely the term that perks up his attention. He’s spent a good deal of his energies on studying a synaptic etiology for autism. Much in the same way my fiancé has been the “Minicolumn Man,” Geschwind is the “Synapse Guy”.
I’ve been reading through his most recent publication in Cell entitled, “Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.” 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.
They went on to look at overlap of genes within these modules with those candidate genes listed within the SFARI database (an autism gene set) and another set of autism-risk genes which were differentially expressed (different from controls) in an earlier study by Voineagu et al. (2011). They found that 25% of the SFARI genes and 42% of the Voineagu et al. genes overlapped with the M13-17 modules. In addition, one of the Gene Ontology (GO) annotation terms (i.e., simple single word terms regarding biological function of a given gene) for this triad of modules is “synaptic transmission”. There’s Geschwind’s red-flag term.
Interestingly, the team also found that when looking at genes that are strictly the result of rare de novo (new) variants (RDNV), those gene products are coexpressed in the M2-3 modules, associated with neurogenesis or transcriptional regulation. They therefore hypothesized that:
“more severe neurodevelopmental consequences would result from disrupting early transcriptional [regulation] during neuronal proliferation and differentiation, as compared with later disruption of synaptic development and neuronal function” (p. 1014).
On the whole, that’s not a bad idea. Although I would also wonder whether, in part, severity of symptomotology ensuing from these mutations might not also be affected by the fact that this group of RDNVs only includes genes with protein-coding disruptions (the SFARI database, at least, includes all sorts of mutations). Mutations which target exons especially within the protein-coding segments, on average, tend to be much more deleterious compared to mutations within promoter, intronic, or intergenic regions which are more likely to affect transcriptional regulation in subtler ways. In any case, an interesting hypothesis.
Even though I haven’t finished sifting through the paper (it’s a bit dense and, after all, I’m a slow reader), a few thoughts have struck me. For one, the authors found that the upper 2/3 layers of the cortex (referred to as the superficial or supragranular layers) where especially enriched in expression of genes within modules M13-17 as compared to the lower layers 4-6. Some of these synaptic-associated genes may well be more specific to certain layers; however, if they are generally synapse-related, then any location which is denser in synapses would be expected to exhibit an enrichment in these gene products. As it turns out, layers 2/3 are particularly synaptically dense [1]. So this enrichment of gene product could simply be a reflection of the number of synapses that varies by layer and not necessarily point towards one layer being more or less severely affected in autism.
Which brings up another point. Even though “synaptic transmission” genes are more highly expressed during synaptogenesis, they are not absent during neurogenesis. And as I discussed briefly last week and have been investigating in my own work, many “synaptic” genes are not solely synaptic but play roles in many if not all aspects of cell growth, from proliferation, to migration, branching, and synapse development. Quite a few of the well-known “synaptic” genes identified in autism are generally associated with cell-to-cell adhesion, whether that occurs between neural stem cells in the cell junction or at the synapse between neurons.
What this touches on is that, even though a gene product may not be “enriched” at a particular location at a given time, that doesn’t mean it isn’t playing a vital role. And especially if it is playing different roles at different times, then quantitating solely by absolute quantity may give a false impression of a gene product’s importance. “Less” doesn’t necessarily mean “less important”.
In any case, a good solid study by Geschwind’s team, even if it does highlight some of his synaptophilia (and my neurogenophilia in turn!). I look forward to reading through it more thoroughly over the coming days and perhaps I may have a few more morsels to comment on next week. Till then, ciao!
