Supplementation with D-serine prevents the onset of cognitive deficits in adult offspring after maternal immune activation

Fujita, Yūkō; Ishima, Tamaki; Hashimoto, Kenji

doi:10.1038/srep37261

Cited by 37 publications

(44 citation statements)

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“…We found cognitive deficits of juvenile offspring from poly(I:C)-treated mice, consistent with previous reports 28 , 29 . Since cognitive impairment is seen in adolescent and young adult with a high risk for psychosis 6 , 7 , it seems that the juvenile offspring after MIA may be at the prodromal stage for psychosis 28 , 29 . Furthermore, we found reduction of PV-IR in the mPFC at juvenile offspring after MIA, which is consistent with the previous study 28 .…”

Section: Discussionsupporting

confidence: 93%

Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after maternal immune activation

Matsuura

Ishima

Fujita

et al. 2018

Sci Rep

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Maternal immune activation (MIA) contributes to behavioral abnormalities relevant to schizophrenia in adult offspring, although the molecular mechanisms underlying MIA-induced behavioral changes remain unclear. Here we demonstrated that dietary intake of glucoraphanin (GF), the precursor of a natural antioxidant sulforaphane, during juvenile and adolescent stages prevented cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial prefrontal cortex (mPFC) of adult offspring after MIA. Gene set enrichment analysis by RNA sequencing showed that MIA caused abnormal expression of centrosome-related genes in the PFC and hippocampus of adult offspring, and that dietary intake of GF improved these abnormal gene expressions. Particularly, MIA increased the expression of suppressor of fermentation-induced loss of stress resistance protein 1 (Sfi1) mRNA in the PFC and hippocampus of adult offspring, and dietary intake of GF prevented the expression of Sfi1 mRNA in these regions. Interestingly, we found altered expression of SFI1 in the postmortem brains and SFI1 mRNA in hair follicle cells from patients with schizophrenia compared with controls. Overall, these data suggest that centrosome-related genes may play a role in the onset of psychosis in offspring after MIA. Therefore, dietary intake of GF-rich vegetables in high-risk psychosis subjects may prevent the transition to psychosis in young adulthood.

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Section: Discussionsupporting

confidence: 93%

Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after maternal immune activation

Matsuura

Ishima

Fujita

et al. 2018

Sci Rep

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“…(35). Previously, we reported that juvenile offspring of prenatal poly(I:C)-treated mice showed cognitive deficits and the reduction of PV-IR in the mPFC (36)(37)(38)(39). Here we examined whether TPPU (15 mg/L) in drinking water during juvenile and adolescent stages [from prenatal day (P) 28 to P56] could prevent cognitive deficits and reduction of PV-IR in the mPFC of adult offspring after MIA.…”

Section: Levels Of Seh and Eicosanoid Metabolites In The Brain From Jmentioning

confidence: 99%

Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation

Ren

Yang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia-and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or EPHX2) mRNA in induced pluripotent stem cellderived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA. epoxy fatty acid | ER stress | iPSCs | maternal infection | prevention E pidemiological studies implicate prenatal environmental factors, including maternal immune activation (MIA), in playing a key role in the etiology of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) (1-7). A number of studies suggest associations between maternal infections or inflammatory biomarkers and schizophrenia and ASD (2-4, 7). For example, there are key epidemiological results supporting associations between maternal infectious pathogens (i.e., influenza virus, herpes simplex virus, Toxoplasma gondii, rubella, and bacterial pathogens) and inflammatory biomarkers (i.e., cytokines and Creactive protein) and schizophrenia (2,7,8). The Finnish Prenatal Studies birth cohort showed that elevated maternal levels of Creactive protein in early to midgestation was related to an increased risk of ASD in offspring (9), although maternal midpregnancy levels of C-reactive protein were related to a decreased risk of ASD (10). A meta-analysis suggests that maternal infection during pregnancy increases the risk of ASD in offspring (4). Collectively, MIA during pregnancy can increase the risk of neurodevelopmental disorders in offspring. The onset of schizop...

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“…Serine racemase knockout mice (SRKOs) show a 90% reduction in cortical D-serine resulting in substantially impaired NMDAR function (Basu et al, 2009). While evidence of the efficacy of glutamatergic agents for the treatment of negative symptoms remains mixed (Buchanan et al, 2017), some human studies report an amelioration of negative and positive and cognitive symptoms, in at-risk populations after D-serine treatment (Fujita, Ishima, & Hashimoto, 2016;Kantrowitz et al, 2010;Stip & Trudeau, 2005). While evidence of the efficacy of glutamatergic agents for the treatment of negative symptoms remains mixed (Buchanan et al, 2017), some human studies report an amelioration of negative and positive and cognitive symptoms, in at-risk populations after D-serine treatment (Fujita, Ishima, & Hashimoto, 2016;Kantrowitz et al, 2010;Stip & Trudeau, 2005).…”

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confidence: 99%

“…SRKOs also exhibit several cognitive and behavioral abnormalities consistent with schizophrenia (Balu et al, 2013). While evidence of the efficacy of glutamatergic agents for the treatment of negative symptoms remains mixed (Buchanan et al, 2017), some human studies report an amelioration of negative and positive and cognitive symptoms, in at-risk populations after D-serine treatment (Fujita, Ishima, & Hashimoto, 2016;Kantrowitz et al, 2010;Stip & Trudeau, 2005). Together, these findings suggest that low levels of D-serine may contribute to schizophrenic symptomatology via a reduction in NMDA receptor function.…”

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confidence: 99%

Sociality deficits in serine racemase knockout mice

et al. 2019

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Background Studies of schizophrenia have pointed to the role of glutamate in its pathophysiology. Mice lacking D‐serine show impairments in neurotransmission through NMDA receptors and display behaviors consistent with features of schizophrenia. Yet, socio‐communicative deficits, a characteristic of schizophrenia, have not been reported in serine racemase knockout mice. Methods We use behavioral testing (the three‐chambered social approach task, the dyadic interaction task, and the novel object recognition task) to examine socio‐communicative behaviors in these mice. Results Serine racemase mice show abnormal social investigation and approach behavior, and differ from wild‐type controls in the duration and number of vocalizations they emit in the presence of a conspecific. Serine racemase knockout mice were not impaired in a cognitive test (novel object recognition), although they displayed abnormal behavior in the acquisition phase of the task. Conclusions Serine racemase knockout mice demonstrate abnormalities in socio‐communicative behaviors consistent with an impairment in sociality, a negative symptom of schizophrenia.

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Supplementation with D-serine prevents the onset of cognitive deficits in adult offspring after maternal immune activation

Cited by 37 publications

References 60 publications

Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after maternal immune activation

Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after maternal immune activation

Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation

Sociality deficits in serine racemase knockout mice

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