A few weeks ago I summarized the findings of our latest study in Frontiers. Unfortunately, I gather as there was almost no interest in the blog that I did a very poor job of explaining why our findings are relevant to the current science of autism. My bad. To rectify that little blunder, I’m using this Sunday’s blog to break down our latest findings and explain why they’re important in continuing the work to understand what autism is at the cellular level.
Science is often a popularity contest, as are most other things in life. As such, the ideas en vogue may be a reflection of their usefulness, but may especially be indicative of which scientists and organizations are “on top” in the hierarchy of scientific competition. This is nothing new to the field. This also means that certain ideas, whether accurate or not, may dominate a field of research for a period of time. Just look at the Refrigerator Mother Theory of autism from the 20th century.
If one has attended the International Meeting for Autism Research for the last several years running, one quickly gets the impression that the bulk of the scientific community has decided that the pathology of autism lies within the synapse. This, my friends, is the hot topic in autism. And it’s not to say that there isn’t strong evidence supporting the role of synaptic dysfunction in the heterogeneous conditions. However, one thing which the bulk of the community seems to be failing to do, in my estimation, is view the development of the neuron as a type of gestalt. Instead, the trends are to dissect portions of the neuron, such as the synapse or dendrite, and treat them as though they’re anatomically separable from the remainder of the cell. As such, we only get photographic glimpses into the life of that cell, which do little to tell us how it developed in the first place.
Work by various neuropathologists, including my husband, have shown that over 90% of brains studied postmortem in autism exhibit disturbances to early neuronal development, such as neurogenesis and pre-migratory maturation. This is particularly apparent in the neocortex and is evidenced by dysplastic structures, heterotopias, etc. In spite of this evidence, the topic is not currently popular and therefore doesn’t typically factor into most theories of autism. Reflective of this, if one were to keyword “autism” + “synapse” into PubMed, you would receive a return of 653 articles, compared to “autism” + “neurogenesis” which returns only 157. Do the same on Google Scholar, and “autism” + “synapse” returns over 20,000 hits, meanwhile “autism” + “neurogenesis” only 12,000.
Illustration of neurogenesis in the developing neocortex of the human brain. Newborn neurons are produced from the ventricular and subventricular zones and then migrate to their final destinations in the cortical plate. Borrowed from Lui et al. (2011).
In this last publication, our greatest concern was rectifying these divergent evidences with one another. In order to understand whether both the neuropathologists and molecular biologists are correct, we took a list of close to 200 high-risk autism-related genes and delved in depth into their involvements at different stages of neuronal development. What we found was that 88% of this core list of genes showed involvement in early stages of neuronal maturation, ranging from neural induction just preceding neurogenesis to pre-migration. Most often this manifest as premature or delayed neurogenesis. However, 80% of these same genes also appeared to influence later stages of post-migratory neuronal differentiation, in terms of neuritic and synaptic developments as well as ongoing plasticity.
In short, this work suggests that the genes implicated in autism tend to affect multiple stages of neuronal development and it’s therefore important that we study development of the neuron in autism more holistically. (We should also study cells other than neurons as well, but that’s a topic for another blog.) This work also indicates that both neuropathologists and molecular biologists are correct, albeit in looking at and describing different sides of the same coin. We’re hoping that this work is a positive step towards integrating these somewhat disparate fields of research.
While I would be one of the first people to admit that the behavioral symptomology of autism is largely due to how the brain connects and communicates within itself, I also believe that many aspects of neuritic and synaptic developments are rooted in earlier processes of neuronal maturation. Therefore, even if we wish to study the synapse in autism, we may still need to look earlier in the neuron’s history in order to do so. In metaphorical terms, I prefer to view the life of a neuron as a long string of molecular dominoes: even when just one domino is out of place, the development of that neuron can be irrevocably altered.
