Referee 1's Review:

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication, the manuscript has been revised in light of these comments and to address other editorial requirements.
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This paper (Zuena et al.) submitted to Plos One is very interesting. It is also a very important one given the questions it raises. Behavioral Neurosciences, Molecular Neurobiology, Experimental Neuropsychiatry use for 75-85 % the same animal models, let's say, adult rats, 300 g, males. Moreover individual differences are still uncommonly considered either within the same sex or when gender is considered. It is of interest to remind that this problem was already considered fifty years ago by Cronbach ("The two disciplines of scientific Psychology", Am Psychologist, 1957) who noticed: "Individual differences have been an annoyance rather than a challenge for the experimenter...For reasons both statistical and philosophical, error variance is to be reduced by any possible device...". Gender differences fall into this type of disfavor. Here Zuena et al., investigate the long-term consequences of prenatal stress in rats and compare male and female offspring. If we except the pioneer work of Ingebord Ward in 1972, a classic never replicated, gender differences for the prenatal stress effects have not been carefully investigated. Moreover, as reviewed in the introduction of the paper, some contradictions still exist in the literature concerning the proper effects of prenatal stress. It is a great pity because it is well known that in neuropsychiatric and behavioral developmental disorders (for which environmental and socioeconomic status play a role) there are clear gender differences.

The goal of the paper was to correlate behavioral responses with neurobiological data focused on the hippocampus region given to be a prenatal restraint stress (PRS) target. In particular three neuronal targets have been investigated: 1) glutamate receptors, 2) BDNF levels, 3) and neurogenesis in the dentate gurus, which are classically correlated with learning processes and in response to stress. In brief Zuena et al., demonstrate that PRS induces inverse effects in male vs female: improvement in female, impairment in male. Stressed females display reduced anxiety (increase in male), spatial learning improvement (nothing in male), increase activity of m Glu 1/5 receptors (reduced in male), but no change in neurogenesis and BDNF levels (increase in male). These data are not in line with the classic relationship between correlative changes in hippocampus and learning abilities in a so-called hippocampus-dependent response.
Techniques are sound; I may regret that the last markers available on the market, more sensitive and selective for neurogenesis have not been used.

Results are clearly documented.

The paper raises unanswered questions. 1) The relations between glutamate receptors and neurogenesis, certainly complex, are waiting for more selective models, 2) Is there a mathematical correlation possible between anxiety and Glu receptors changes? Are pharmacological investigations with selective ago/antagonists possible? 3) Some papers have shown a relation between glucocorticoids and glutamate transmissions: have the authors checked the HPA axis of their animals?

Results concerning learning performance are very interesting and provocative but a bit disturbing, and the data obtained with males are not classic: changes in spatial learning appear sometimes with the passage of time (not discussed). The almost absence of relation between female improvement with the biological markers investigated is a new information.

In conclusion, the data are very important and not questionable. They change one mind about the prenatal stress effects.

Introduction and discussion, sometimes difficult to read, may be improved.
The paper is completed with a long list of references. However I think that Introduction and Discussion sections might be enriched by citing and discussing papers published by Luine V.N., Conrad, C.D., Galea, L.A.M., Viau, V., Sternberg, W.F., Sascher, N., Patchev, V.K., and Bowman, R.E. Some of these references are in Bowman, R.E., J. Neuroendocrinology, 2005, 17, 526-535. Readers will also be grateful to find these references.

The paper is worth publishing in Plos One. I warmly recommend this nice piece of Science.