Neurodevelopmental disorders, including autism spectrum disorder (ASD), arise from complex interactions between genetic and environmental factors. Maternal immune activation (MIA) is a key environmental risk factor that disrupts embryonic neurodevelopment, primarily through inflammatory cytokines. However, the contribution of non-inflammatory cytokines, particularly hematopoietic growth factors, remains poorly understood. Here, we identified granulocyte colony-stimulating factor (G-CSF) as a candidate mediator of MIA-induced neurodevelopmental alterations. Polyinosinic:polycytidylic acid [poly(I:C)] administration to pregnant dams at embryonic day 12.5 (E12.5) significantly increased G-CSF levels in both maternal plasma and embryonic tissue. To assess its contribution to neurodevelopmental alterations, we administered human G-CSF (hG-CSF) to pregnant dams at E12.5. At the structural level, male offspring exposed to prenatal hG-CSF showed increased dendritic spine density and a higher proportion of immature spines in the medial prefrontal cortex. Behaviorally, both male and female offspring exhibited altered social preference. Bulk RNA-seq analysis of the prefrontal cortex revealed altered enrichment of pathways related to synapse organization, translation, and mitochondrial function in both sexes, with opposite directions of enrichment in males and females. In vitro, G-CSF attenuated synapse maturation and enhanced microglial phagocytic activity. These findings suggest that G-CSF may contribute to MIA-associated neurodevelopmental alterations, potentially through disrupted synapse maturation and microglial function. Our results highlight a hematopoietic pathway that may contribute to mechanisms underlying neurodevelopmental disorders, including ASD.

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that regulates lipid metabolism and inflammatory responses. Recent studies have revealed that PPARα also plays an important role in maintaining neuronal homeostasis through modulation of fatty-acid oxidation and inflammation in the brain. Our previous work using both animal models and human samples has demonstrated that PPARα is involved in the pathophysiology of schizophrenia. Ppara-deficient mice exhibit reduced prepulse inhibition, increased anxiety-like behavior, and decreased dendritic spine density with a reduction of mature spines in the prefrontal cortex. In patients with schizophrenia, decreased expression of the PPARA gene in hair-follicle cells and loss-of-function variants of PPARA have been identified, suggesting that impairment of PPARα signaling contributes to disease development. Moreover, administration of a PPARα agonist ameliorates dendritic spine abnormalities and behavioral deficits in phencyclidine (PCP)-treated model mice. Other groups have reported that prenatal treatment with PPARα agonists improves adult behavioral abnormalities and suppresses fetal cytokine elevation in maternal immune-activation models. In addition, PPARα agonists have shown beneficial effects in animal models and clinical studies of autism spectrum disorder and depression. Collectively, these findings indicate that PPARα represents a novel therapeutic target that bridges metabolic, neurodevelopmental, and neurodegenerative mechanisms, offering new opportunities for drug discovery in psychiatric and neurological disorders.

BACKGROUND: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on pituitary function remains unclear, particularly during the acute phase of coronavirus disease 2019 (COVID-19). CASE PRESENTATION: We report the case of a 40-year-old man with arginine vasopressin deficiency (central diabetes insipidus) who was admitted for the evaluation of anterior pituitary function. The patient developed mild COVID-19 during the hospitalization, when we inadvertently observed rapid activation of the hypothalamic-pituitary-adrenal (HPA) axis prior to the onset of fever. At the estimated onset of COVID-19, the patient's body temperature and the serum level of C-reactive protein remained within normal limits, whereas plasma ACTH levels drastically elevated, and subsequently, serum cortisol levels remain consistently high throughout the day, resulting in increased urinary free cortisol. The serum levels of several cytokines, including IFN-γ, IL-1RA, IL-6, and TNF-α, were also significantly elevated compared to those in the non-infected state. Acute suppression of thyroid and gonadal functions was observed approximately one day after the HPA axis activation. CONCLUSIONS: These findings illustrate the rapid response of the HPA axis to inflammatory factors in the early-stage COVID-19, which may have important implications for understanding the initial host responses to SARS-CoV-2 infection.

Fatty acid-binding protein 4 (FABP4), a key regulator of lipid metabolism and inflammation, has been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). This study investigated the effects of FABP4 inhibition during gestation and lactation on offspring neurodevelopment using the selective FABP4 inhibitor BMS309403. Female mice received BMS309403 (15 mg/kg) via oral gavage from two weeks before mating to postnatal day 28 (P28). Administration of BMS309403 to mouse dams resulted in autism-like phenotypes in male offspring (behavioral tests: n = 7-10 per group; spine analysis: 6 mice per group, n = 26-38 dendrites per group), characterized by increased dendritic spine density in the prefrontal cortex, impaired vocal communication, increased repetitive behaviors, and depression-like symptoms. Fatty acid analysis (n = 4-6 per group) revealed significant alterations in maternal and fetal lipid profiles, including elevated arachidonic acid levels in maternal plasma and increased n6PUFAs in the fetal brain, suggesting a pro-inflammatory lipid environment. Principal component analysis demonstrated distinct clustering of lipid profiles between control and BMS309403-treated groups. Cytokine analysis (n = 6 per group) indicated reductions in IL-10 and IL-12(p40) in maternal plasma and decreased TNFα in the fetal plasma, suggesting dysregulation in systemic inflammatory signaling. These findings suggest that FABP4 inhibition during the perinatal period perturbs lipid metabolism and may influence neurodevelopment through systemic metabolic changes. Although the direct effects of BMS309403 on the fetal brain cannot be excluded, alteration in maternal metabolism and placental function may have contributed to the observed neurodevelopmental changes in offspring.