Although PPI has been most frequently studied in schizophrenia, impairments have also been observed in patients with neuropsychiatric disorders including bipolar disorder, autism and Tourette syndrome 
, suggesting that PPI defects may be a shared neural dysfunction across the current diagnostic categories of mental disorders. Therefore, in this study, we targeted PPI as a behavioral phenotype that is highly relevant to psychiatric illnesses and may constitute an important aspect of the pathophysiology of these diseases.
In this study, we have shown that postnatal neurogenesis can be impaired by an environmental milieu, MAM-treatments, in addition to gene disruptions (Pax6
in the current study) in rats. In addition, we reveal for the first time that even postnatal MAM administration can induce PPI deficits. It is already known that the MAM-induced decrease in fetal neurogenesis can cause PPI deficits 
. The current findings also suggest that once postnatal neurogenesis is impaired, at the developmental period equivalent to adolescence in humans even if neurogenesis recovers later in life, the susceptibility for PPI deficits remains. This may mean that a ‘critical period’ for the formation of neural circuits underlying PPI spans at least 4–5 weeks in rats. The 4–5 week-old rats show salient neurogenesis 
. However, because we did not examine other developmental periods for MAM-treatments, we recognize the need for further studies to determine the chronological relationship between impaired neurogenesis and reduced PPI.
It is noteworthy that the administration of ARA successfully and dramatically increased neurogenesis not only in wild-type but also Pax6
(+/−) rats. It is known that prostaglandin E2 (PGE2) plays an important role in neurogenesis 
, stimulates CB2, a receptor for endocannabinoids and promotes mouse neural stem cell proliferation 
. Both PGE2 and endocannabinoids are metabolites of ARA. It is also possible that ARA itself augments proliferation of neural progenitor cells. ARA could be transmitted from Fabps to nuclear receptor proteins 
, thereby indirectly controlling the transcription of genes related to cell proliferation. This scenario is analogous to that where retinoic acid (a metabolite of vitamin A) is transmitted from a cellular retinoic acid binding protein and Fabp5 to nuclear receptors RAR and PPARβ/δ, respectively 
. We also speculate from our current study that the effect of DHA albeit small, may be caused by promoting differentiation and prevention of apoptosis, rather than by increasing cell proliferation [Figures S7B, S7D
. The precise mechanisms for the role of PUFAs in fostering neurogenesis, however, warrants further studies.
Treating the Pax6
(+/−) rats with ARA for 15 weeks from birth, we were able to alleviate their PPI defects. Because this was the first attempt to evaluate the effects of ARA on PPI, we administered ARA long term to obtain an unequivocal and maximum outcome. There are several possibilities of how ARA can prevent or restore PPI defects in our model rodents. One explanation is that ARA affects postnatal neurogenesis in several brain regions including the hippocampus, and eventually leads to modifications of the neural circuitry of PPI [see Figure S1
and Table S2
]. It may not be excluded another explanation, for example, that ARA can directly influence the fluidity of neuronal membranes, thereby regulating neuronal transmission 
because ARA was continuously administered until scoring PPI. In this case, we may have to consider the roles of Fabp3 also. Fabp3 is expressed in mature neurons in the dentate gyrus (our unpublished results) and reported to have a substantial affinity to ARA 
On one hand, the recovery of PPI was not complete in the Pax6
(+/−) rats. It is likely that the multiple neuro-functional disturbances caused by the gene defect cannot be fully compensated for by postnatal nutritional interventions. In contrast to Mendelian disorders that are usually caused by single gene defects and often manifest with serious physical and/or intellectual abnormalities without effective cures, predisposition to functional psychiatric illnesses is generally associated with multiple susceptibility gene variants with small to modest effects 
. Therefore, we believe that the improved PPI demonstrated in this study (albeit not complete in gene-disrupted rats), could be meaningful when developing risk-reducing measures for mental disorders.
There are numerous clinical studies reporting symptomatic improvements of schizophrenia and other mental illnesses including mood disorders when PUFAs are given in combination with psychotropic drugs, although PUFAs alone are not sufficient as therapeutic agents 
. Such PUFAs are exclusively n-3 fatty acids like EPA (eicosapenteanoic acid) and DHA. The currently observed beneficial effects of ARA may due to the period of administration, i.e. an early postnatal stage, which is different from those examined in human studies. Interestingly it has been reported that patients with schizophrenia show a reduced niacin (vitamin B3) skin flush response, although there is wide inter-individual variation 
. In this test, varying concentrations of niacin are applied to forearm skin and the flush response is rated 
. A decreased flush response is deemed to be a peripheral marker of disturbed lipid-ARA pathways 
There are two large epidemiological studies demonstrating that when pregnant mothers suffered from famine, the risk of their offspring developing schizophrenia increased to two fold 
. As a potential mechanism, Heijman et al. recently reported that individuals who were prenatally exposed to famine in Holland had, 6 decades later, less DNA methylation of an imprinted gene compared with their unexposed, same-sex siblings 
. Therefore, relationship between ARA treatments (and their timing) and epigenetic changes would make a compelling topic for future research. Although multiple nutrients are needed for healthy brain development and maintenance, our current results suggest that an adequate maternal dietary intake of ARA may be especially important for reducing the vulnerability of brains to mental illnesses.
Dietary ARA is a PUFA that can be transmitted directly into the brain via the blood-brain barrier and occurs naturally in nourishing foods such as meat, eggs, fish and seaweed. ARA would therefore appear to be a beneficial molecule for promoting neurogenesis and PPI integrity in a safer way than many artificial compounds. We hope that future studies address the possibility that PUFAs given to lactating mothers (and to young children up to puberty) may reduce the burden of psychiatric diseases including schizophrenia 
. These studies should clarify the untested issues including the optimal ratio of n-3
, the total dosage of PUFAs, the time of intervention and period of administration.