Caution: While this is a cool study in Nature Neuroscience, almost all facets of this work are based on a single fully inbred strain of mouse—-C57BL/6J. This s

Caution: While this is a cool study in Nature Neuroscience, almost all facets of this work are based on a single fully inbred strain of mouse—-C57BL/6J. This strain also happens to have a major mutation in the GABRA2 gene that reduces expression about 2X relative to almost all other strains of mice. GABRA2 is one of the most important receptors involved in inhibitory responses in CNS and benzodiazepine responses. This same strain also has a well known splice variant mutation in a key mitochondrial gene, NNT, that modulates both mitochondrial and macrophage function. The microglial mentioned in this paper are a special class of macrophages that reside in the CNS. Given these comments, when the authors refer to “wild type” (WT) mice, remember these are anything but true wild type mice. Fully inbred strains always carry numerous homozygous recessive and dominant mutations (several hundred each) that often affect CNS, immune systems, and mitochondrial functions. The results may well hold up in other strains, but I would not count on it. Do benzodiazepines affect all humans uniformly? Would studies of other strains or types have been practical? Yes. The Thy1-GFP and Thy1-YFP lines can be crossed to make F1 hybrids. This particular transgene is also available on at least one other strain of mouse (DBA/2J). Unfortunately, most reviewers at Nature Neuroscience are not geneticists ;-) They are typically strong molecular neurobiologists who are used to reductionist methods. They are perfectly content with submission to Nature journals that are based entirely on with N=1 mouse genome—almost always the mutant C57BL/6J inbred strain. In my own work I try to avoid this N=1 trap. (But I have also failed ;-) Generality and robustness of results (see quote below) should ideally be established across two or more diverse genomes before making broad claims of relevance to other species, including od course to humans. The quote: “We have demonstrated that microglia in WT mice alter their morphology and functions upon diazepam treatment and cease to do so in Tspo−/− mice.”