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Schizophrenia is a mental disorder with sex bias in disease onset and symptom severity. Recently, it was observed that females present more severe symptoms in the perimenstrual phase of the menstrual cycle. The administration of estrogen also alleviates schizophrenia symptoms. Despite this, little is known about symptom fluctuation over the menstrual cycle and the underlying mechanisms. To address this issue, we worked with the two-hit schizophrenia animal model induced by neonatal exposure to a virus-like particle, Poly I:C, in association with peripubertal unpredictable stress exposure. Prepulse inhibition of the startle reflex (PPI) in male and female mice was considered analogous to human schizophrenia-like behavior. Female mice were studied in the proestrus (high-estrogen estrous cycle phase) and diestrus (low-estrogen phase). Additionally, we evaluated the hippocampal mRNA expression of estrogen synthesis proteins, TSPO and aromatase, and estrogen receptors ERα, ERβ, and GPER. We also collected Peripheral Blood Mononuclear Cells (PBMCs) from male and female patients with schizophrenia and converted them to induced microglia-like cells (iMGs) to evaluate the expression of GPER. We observed raised hippocampal expression of GPER in two-hit female mice at the proestrus phase without PPI deficits and higher levels of proteins related to estrogen synthesis, TSPO, and aromatase. In contrast, two-hit adult males with PPI deficits presented lower hippocampal mRNA expression of TSPO, aromatase, and GPER. iMGs from male and female patients with schizophrenia showed lower mRNA expression of GPER than controls. Therefore, our results suggest that GPER alterations constitute an underlying mechanism for sex influence in schizophrenia.

The current drug therapy for schizophrenia effectively treats acute psychosis and its recurrence; however, this mental disorder's cognitive and negative symptoms are still poorly controlled. Antipsychotics present important side effects, such as weight gain and extrapyramidal effects. The essential oil of Alpinia zerumbet (EOAZ) leaves presents potential antipsychotic properties that need further preclinical investigation. Here, we determined EAOZ effects in preventing and reversing schizophrenia-like symptoms (positive, negative, and cognitive) induced by ketamine (KET) repeated administration in mice and putative neurobiological mechanisms related to this effect. We conducted the behavioral evaluations of prepulse inhibition of the startle reflex (PPI), social interaction, and working memory (Y-maze task), and verified antioxidant (GSH, nitrite levels), anti-inflammatory [interleukin (IL)-6], and neurotrophic [brain-derived neurotrophic factor (BDNF)] effects of this oil in hippocampal tissue. The atypical antipsychotic olanzapine (OLZ) was used as standard drug therapy. EOAZ, similarly to OLZ, prevented and reversed most KET-induced schizophrenia-like behavioral alterations, i.e., sensorimotor gating deficits and social impairment. EOAZ had a modest effect on the prevention of KET-associated working memory deficit. Compared to OLZ, EOAZ showed a more favorable side effects profile, inducing less cataleptic and weight gain changes. EOAZ efficiently protected the hippocampus against KET-induced oxidative imbalance, IL-6 increments, and BDNF impairment. In conclusion, our data add more mechanistic evidence for the anti-schizophrenia effects of EOAZ, based on its antioxidant, anti-inflammatory, and BDNF up-regulating actions. The absence of significant side effects observed in current antipsychotic drug therapy seems to be an essential benefit of the oil.

Polymorphisms in the human dopamine transporter (DAT) are associated with bipolar endophenotype. Based on this, the acute inhibition of DAT using GBR12909 causes behavioral alterations that are prevented by valproate (VAL), being related to a mania-like model. Herein our first aim was to analyze behavioral and brain oxidative alterations during a 24 h period post-GBR12909 to better characterize this model. Our second aim was to determine the preventive effects of lithium (Li) or VAL 2 h post-GBR12909. For this, adult male mice received GBR12909 or saline being evaluated at 2, 4, 8, 12 or 24 h post-administration. Hyperlocomotion, levels of reduced glutathione (GSH) and lipid peroxidation in brain areas were assessed at all these time-points. GBR12909 caused hyperlocomotion at 2 and 24 h. Rearing behavior increased only at 2 h. GSH levels decreased in the hippocampus and striatum at the time points of 2, 4, 8 and 12 h. Increased lipid peroxidation was detected at the time-points of 2 and 12 h in all brain areas studied. At the time-point of 2 h post-GBR12909 Li prevented the hyperlocomotion and rearing alterations, while VAL prevented only rearing alterations. Both drugs prevented pro-oxidative changes. In conclusion, we observed that the main behavioral and oxidative alterations took place at the time-period of 2 h post-GBR12909, what points to this time-period as the best for the assessment of alterations in this model. Furthermore, the present study expands the predictive validity of the model by the determination of the preventive effects of Li.

Early-life challenges, particularly infections and stress, are related to neuropsychiatric disorders such as autism and schizophrenia. Here, we conducted a wide range of behavioral tests in periadolescent (postnatal day (PN) 35) and adult (PN70) Swiss mice neonatally challenged with LPS on PN5 and -7, to unveil behavioral alterations triggered by LPS exposure. Immune and neurotrophic (brain-derived neurotrophic factor-BDNF) alterations were determined in the prefrontal cortex (PFC), hippocampus (HC), and hypothalamus (HT). Since the incidence and clinical manifestations of neurodevelopmental disorders present significant sex-related differences, we sought to distinctly evaluate male and female mice. While on PN35, LPS-challenged male mice presented depressive, anxiety-like, repetitive behavior, and working memory deficits; on PN70, only depressive- and anxiety-like behaviors were observed. Conversely, females presented prepulse inhibition (PPI) deficits in both ages studied. Behavioral changes in periadolescence and adulthood were accompanied, in both sexes, by increased levels of interleukin (IL-4) (PFC, HC, and HT) and decreased levels of IL-6 (PFC, HC, and HT). BDNF levels increased in both sexes on PN70. LPS-challenged male mice presented, in both ages evaluated, increased HC myeloperoxidase activity (MPO); while when adult increased levels of interferon gamma (IFNγ), nitrite and decreased parvalbumin were observed. Alterations in innate immunity and parvalbumin were the main LPS-induced remarks between males and females in our study. We concluded that neonatal LPS challenge triggers sex-specific behavioral and neurochemical alterations that resemble autism spectrum disorder, constituting in a relevant model for the mechanistic investigation of sex bias associated with the development of this disorder.