Again, we’re behind on blogging – you guys are keeping us busy with great neuroscience – but here is the story of a pair of papers that appeared back to back in last week’s issue and a continuation of the discussion started here by Noah about the process of joint publication. The two papers by Tobias Boeckers and colleagues and by Eunjoon Kim and colleagues were independently submitted and both describe autism-like phenotypes of mice with mutations in the gene Shank2. In human studies, SHANK2 has been associated with rare cases of autism and these two mice add to the ever-growing list of rodents (according to SFARI.org, 17 rodent models debuted in 2011 alone) that are being created to investigate the functional consequences of genetic mutations linked to autism, in the hopes of understanding mechanisms underlying core symptoms. Shank2 is a scaffolding protein that regulates excitatory synapse function by holding together various molecules such as neurotransmitter receptors and signaling proteins. Mutations in another member of the same gene family, SHANK3, are also associated with human autism, and mutant mice display behaviors reminiscent of ASD symptoms, such as social deficits and obsessive behavior. So this protein family, and more generally, glutamatergic transmission, is potentially one promising line of investigation.
Each of today’s papers describe mice with striking behavior (hyperactivity and social deficits) and alterations in excitatory neuronal activity. And that’s where things start to get (even more) interesting. The mice carry very similar genetic mutations, and have similar behavior, yet are opposite in some aspects of electrophysiology. Boeckers and colleagues report enhanced NMDA receptor-mediated excitatory currents, Kim and colleagues a reduction. Kim also found that restoring NMDAR function pharmacologically improves social deficits, but not other behaviors.
A lot of science we could discuss here… but on to editorial issues. Both papers had what one of my former advisors used to call “a difficult birthing process”. Both were rejected at some point, and successfully appealed after inclusion of additional data to strengthen existing conclusions and to extend the studies conceptually. There was discussion of whether the individual components (from molecular to electrophysiology to behavior) of the studies told sufficiently consistent a story. There was discussion of whether the requirement for conceptual advance (i.e. mechanism) needed to raised in light of the existing work on Shank3. And much much more… but obviously, in the end, we agreed that both papers deserved to be published, even though the inconsistent electrophysiology left a question mark. As the papers were not co-submitted, we did not ask that the authors attempt to reconcile the differences. All we could and did do was to seek overlapping reviewers to ascertain, to the best they could tell, that each study was technically sound. Once that had been determined, we did our best to coordinate their appearance by publishing back to back in print (one paper was accepted and published online earlier). In cases where papers ARE formally co-submitted, and therefore we assume all authors are aware of each others’ results, we do sometimes ask that the authors attempt to resolve discrepancies between studies or perform direct comparisons in the interests of advancing the overall scientific picture. One recent example is a trio of exome sequencing papers (coincidentally, also about autism) we published a few months ago. In that case, one of the reviewers requested that the authors compare and cross-reference their results, which they graciously did.
In the case of the Shank2 papers, the papers were highly conceptually related and accepted within weeks of each other, so the case for joint publication was obvious. The situation gets more complicated when papers are at very different stages of the process but that will have to be the topic for another day. Watch this space…