ZFP804A mutant mice display sex-dependent schizophrenia-like behaviors.

Genome-wide association studies uncovered the association of ZNF804A (Zinc-finger protein 804A) with schizophrenia (SZ). In vitro data have indicated that ZNF804A might exert its biological roles by regulating spine and neurite morphogenesis. However, no in vivo data are available for the role of ZNF804A in psychiatric disorders in general, SZ in particular. We generated ZFP804A mutant mice, and they showed deficits in contextual fear and spatial memory. We also observed the sensorimotor gating impairment, as revealed by the prepulse inhibition test, but only in female ZFP804A mutant mice from the age of 6 months. Notably, the PPI difference between the female mutant and control mice was no longer existed with the administration of Clozapine or after the ovariectomy. Hippocampal long-term potentiation was normal in both genders of the mutant mice. Long-term depression was absent in male mutants, but facilitated in the female mutants. Protein levels of hippocampal serotonin-6 receptor and GABAB1 receptor were increased, while those of cortical dopamine 2 receptor were decreased in the female mutants with no obvious changes in the male mutants. Moreover, the spine density was reduced in the cerebral cortex and hippocampus of the mutant mice. Knockdown of ZFP804A impaired the neurite morphogenesis of cortical and hippocampal neurons, while its overexpression enhanced neurite morphogenesis only in the cortical neurons in vitro. Our data collectively support the idea that ZFP804A/ZNF804A plays important roles in the cognitive functions and sensorimotor gating, and its dysfunction may contribute to SZ, particularly in the female patients.

Ventricular Netrin-1 deficiency leads to defective pyramidal decussation and mirror movement in mice.

The corticospinal tract (CST) is the principal neural pathway responsible for conducting voluntary movement in the vertebrate nervous system. Netrin-1 is a well-known guidance molecule for midline crossing of commissural axons during embryonic development. Families with inherited Netrin-1 mutations display congenital mirror movements (CMM), which are associated with malformations of pyramidal decussation in most cases. Here, we investigated the role of Netrin-1 in CST formation by generating conditional knockout (CKO) mice using a Gfap-driven Cre line. A large proportion of CST axons spread laterally in the ventral medulla oblongata, failed to decussate and descended in the ipsilateral spinal white matter of Ntn1Gfap CKO mice. Netrin-1 mRNA was expressed in the ventral ventricular zone (VZ) and midline, while Netrin-1 protein was transported by radial glial cells to the ventral medulla, through which CST axons pass. The level of transported Netrin-1 protein was significantly reduced in Ntn1Gfap CKO mice. In addition, Ntn1Gfap CKO mice displayed increased symmetric movements. Our findings indicate that VZ-derived Netrin-1 deletion leads to an abnormal trajectory of the CST in the spinal cord due to the failure of CST midline crossing and provides novel evidence supporting the idea that the Netrin-1 signalling pathway is involved in the pathogenesis of CMM.

Maternal urban particulate matter exposure and signaling pathways in fetal brains and neurobehavioral development in offspring.

It is well understood that exposure to particulate matter (PM) can have adverse effects on the nervous system. When pregnant women are exposed to PM, their fetuses are also affected through the placenta. However, the mechanisms by which fetal brain development is regulated between mother and fetus remain unclear. C57BL/6J pregnant mice were exposed to PM at embryonic day (E) 2.5, 5.5, 8.5, 11.5, 14.5, and 17.5 via nasal drip at three doses (3, 6, 12 mg/kg of body weight) or PBS control. Neurobehavioral changes in the offspring were examined at 5-6-week-old by open field test (OFT) and elevated plus maze (EPM). The maternal and fetal brain and placenta were collected at E18.5, and molecular signal changes were explored using transcriptome analysis. We found that both male and female low-dose pups and male middle-dose pups traveled a significantly longer distance than controls in EPM tests. Both male and female low-dose pups showed a higher frequency of entering the center area and female low-dose pups exhibited a higher percentage of distance moved in the center area than controls in OFT tests. Gene expression in the maternal brain, fetal brain, and placenta at E18.5 was altered. Differentially expressed genes were enriched in the neuroactive ligand-receptor interaction pathway in all three tissue types. Pathway analysis revealed that the PI3K-Akt and PKC signaling was dysregulated in the fetal brain in the high-dose group compared with the control group. The pathways play a role in neuronal survival and apoptosis. Furthermore, there is a dose-dependent increase in Caspase-6, neuronal apoptosis and neurodegeneration biomarker, levels in E18.5 fetal brain (P = 0.06). In conclusion, our study demonstrated that prenatal PM exposure enhanced exploration and locomotor activity in adolescent offspring and altered molecular events in maternal brain, fetal brain, and placenta. The connections of these changes warrant further investigations.

Negative air ion exposure ameliorates depression-like behaviors induced by chronic mild stress in mice.

The presence of negative air ions (NAI) is suggested to be a beneficial factor in improving psychological status and used in treating depression as an alternative approach. However, more biological evidence from animal models is needed to ensure the effects of NAI on the mood regulation, through which can facilitate identification of possible underlying mechanisms. In this study, the chronic mild stress (CMS) protocol was used to induce depressive-like behaviors in mice, and the effects of NAI exposure on CMS-induced depression-like behaviors were examined. Thirty-day NAI exposure prevented the CMS-induced depression-like behaviors as shown by the restoration of sucrose preference and reduced immobility time in the tail suspension test. In addition, the elevation of serous corticosterone was present in CMS-treated mice but not existed in those with the NAI exposure. Furthermore, we observed altered ratios of some cytokines secreted by type 1 T helper (Th1) cells and Th2 cells in CMS-treated mice, but it could be restored after NAI exposure. In conclusion, NAI intervention is able to ameliorate CMS-induced depression-like behaviors in mice, and this effect is associated with the alteration of corticosterone and functional rebalance between Th1 and Th2 cells.

ELISA analysis of urinary nephrin and podocalyxin standardized by aquaporin-2 in adult patients with nephrotic syndrome.

OBJECTIVE: To investigate urinary nephrin and podocalyxin standardized by aquaporin (AQP)-2 using the enzyme-linked immunosorbent assay (ELISA) method in adult nephrotic syndrome (NS) patients. METHODS: In 107 adult NS patients (27 proliferative nephritis, 77 non-proliferative, and 3 amyloidosis) undergoing renal biopsy, urinary nephrin, podocalyxin and AQP2 were measured by ELISA. Urinary nephrin and podocalyxin were standardized by AQP2 (neph/AQP and PCX/AQP) and values were compared with 11 healthy controls. RESULTS: Urinary neph/AQP correlated positively to PCX/AQP (r = 0.51, p < 0.001). Urinary neph/AQP and PCX/AQP were lower in controls than NS patients. Both proliferative and non-proliferative NS patients excreted high urinary neph/AQP and PCX/AQP without a significant difference between them (p > 0.05). Patients with focal segmental glomerular sclerosis (FSGS) excreted higher urinary neph/AQP (p = 0.09) and PCX/AQP (p < 0.05) compared to the other patients. Urinary neph/AQP and PCX/AQP were increased in the immunoglobulin M nephropathy patients. Amyloidosis patients excreted lower neph/AQP and PCX/AQP. The sensitivity was 0.87 and specificity 0.37 when the neph/AQP borderline value of 0.16 was adopted [area under the curve (AUC) = 0.61]. The sensitivity was 0.74 and specificity 0.61 when the PCX/AQP borderline value was 3.06 (AUC = 0.69). CONCLUSIONS: Urinary neph/AQP and PCX/AQP are increased in NS patients, with FSGS patients showing the highest levels. To distinguish FSGS from other NS forms, the measurement of urinary PCX/AQP may be a practical method, and superior to neph/AQP.