The dissociative anesthetic ketamine elicits symptoms of schizophrenia at subanesthetic doses by blocking N-methyl-Daspartate receptors (NMDARs). This property led to a variety of studies resulting in the now well-supported theory that hypofunction of NMDARs is responsible for many of the symptoms of schizophrenia. However, the roles played by specific NMDAR subunits in different symptom components are unknown. To evaluate the potential contribution of GluN2D NMDAR subunits to antagonist-induced cortical activation and schizophrenia symptoms, we determined the ability of ketamine to alter regional brain activity and gamma frequency band neuronal oscillations in wild-type (WT) and GluN2D-knockout (GluN2D-KO) mice. In WT mice, ketamine (30 mg/kg, i.p.) significantly increased [14 C]-2-deoxyglucose ([ 14 C]-2DG) uptake in the medial prefrontal cortex (mPFC), entorhinal cortex and other brain regions, and decreased activity in the somatosensory cortex and inferior colliculus. In GluN2D-KO mice, however, ketamine did not significantly increase [14 C]-2DG uptake in any brain region examined, yet still decreased [14 C]-2DG uptake in the somatosensory cortex and inferior colliculus. Ketamine also increased locomotor activity in WT mice but not in GluN2D-KO mice. In electrocorticographic analysis, ketamine induced a 111% 6 16% increase in cortical gamma-band oscillatory power in WT mice, but only a 15% 6 12% increase in GluN2D-KO mice. Consistent with GluN2D involvement in schizophrenia-related neurologic changes, GluN2D-KO mice displayed impaired spatial memory acquisition and reduced parvalbumin (PV)-immunopositive staining compared with control mice. These results suggest a critical role of GluN2D-containing NMDARs in neuronal oscillations and ketamine's psychotomimetic, dissociative effects and hence suggests a critical role for GluN2D subunits in cognition and perception.
Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2C-containing NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition. Specifically, pyramidal neurons in the medial prefrontal cortex (mPFC) of GluN2C knockout mice have reduced mEPSC frequency and dendritic spine density and a contrasting higher frequency of mIPSCs. In addition a greater number of perisomatic GAD67 puncta was observed suggesting a potential increase in parvalbumin interneuron inputs. At a network level the GluN2C knockout mice were found to have a more robust increase in power of oscillations in response to NMDAR blocker MK-801. Furthermore, GluN2C heterozygous and knockout mice exhibited abnormalities in cognition and sensorimotor gating. Our results demonstrate that loss of GluN2C subunit leads to cortical excitatory-inhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders.
N-methyl-D-aspartate receptors (NMDARs) are widely distributed in the brain with high concentrations in the telencephalon where they modulate synaptic plasticity, working memory, and other functions. While the actions of the predominate GluN2 NMDAR subunits, GluN2A and GluN2B are relatively well understood, the function of GluN2C and GluN2D subunits in the telencephalon is largely unknown. To better understand the possible role of GluN2C subunits, we used fluorescence in situ hybridization (FISH) together with multiple cell markers to define the distribution and type of cells expressing GluN2C mRNA. Using a GluN2C-KO mouse as a negative control, GluN2C mRNA expression was only found in non-neuronal cells (NeuN-negative cells) in the hippocampus, striatum, amygdala, and cerebral cortex. For these regions, a significant fraction of GFAP-positive cells also expressed GluN2C mRNA. Overall, for the telencephalon, the globus pallidus and olfactory bulb were the only regions where GluN2C was expressed in neurons. In contrast to GluN2C, GluN2D subunit mRNA colocalized with neuronal and not astrocyte markers or GluN2C mRNA in the telencephalon (except for the globus pallidus). GluN2C mRNA did, however, colocalize with GluN2D in the thalamus where neuronal GluN2C expression is found. These findings strongly suggest that GluN2C has a very distinct function in the telencephalon compared to its role in other brain regions and compared to other GluN2-containing NMDARs. NMDARs containing GluN2C may have a specific role in regulating L-glutamate or D-serine release from astrocytes in response to L-glutamate spillover from synaptic activity.
Fat-soluble vitamins (FSVs) are micronutrients essential in maintaining normal physiological function, metabolism and human growth. Ongoing increased awareness regarding FSV concentrations and their impact on human growth along with disease progression warrant the need of developing selective and sensitive analytical methods. LC–MS/MS is currently the method of choice for accurate quantitation of FSVs. However, there are multiple approaches for extraction, separation and calibration of FSVs in biological matrices. This review discusses recent LC–MS/MS methods for the simultaneous quantification of FSVs in biological matrices and summarizes sample pretreatment procedures, chromatographic conditions and calibration approaches. Current challenges and clinical applications in various disease states are also highlighted.
Vitamin K is an essential nutrient in the body and involved in numerous physiological and pathophysiological functions. Both the lack and surplus of vitamin K can put human health at risk. Therefore, it becomes necessary to monitor vitamin K concentrations in different biomatrices through establishing sensitive and specific analytical methods. This review collectively describes an updated overview of the sample pretreatment methodologies and methods for quantitative determination of vitamin K that have been used in last two decades. High Performance Liquid Chromatography (HPLC) is commonly utilized as a standard for separation of vitamin K in combination with different detection including spectroscopic, spectrometric, fluorometric and mass spectroscopy. Recent progress in sample pretreatment technologies and quantitation methodologies have enhanced the ability to identify and quantitate vitamin K in biomatrices to further advance our understanding of the role of this vitamin in human health and disease.
Emodin is the main toxic component in Chinese medicinal herbs such as rhubarb. Our previous studies demonstrated that genetic polymorphisms of UDP-glucuronosyltransferase 2B7 (UGT2B7) had an effect on the glucuronidation and detoxification of emodin. This study aimed to reveal the transcriptional regulation mechanism of UGT2B7 on emodin glucuronidation and its effect on toxicity. Emodin glucuronic activity and genome and transcriptome data were obtained from 36 clinical human kidney tissues. The genome-wide association studies (GWAS) identified that four single nucleotide polymorphisms (SNPs) (rs6093966, rs2868094, rs2071197, and rs6073433), which were located on the hepatocyte nuclear factor 4α (HNF4A) gene, were significantly associated with the emodin glucuronidation (p < 0.05). Notably, rs2071197 was significantly associated with the gene expression of HNF4A and UGT2B7 and the glucuronidation of emodin. The gene expression of HNF4A showed a high correlation with UGT2B7 (R 2 = 0.721, p = 5.83 × 10 −11 ). The luciferase activity was increased 7.68-fold in 293T cells and 2.03-fold in HepG2 cells, confirming a significant transcriptional activation of UGT2B7 promoter by HNF4A. The knockdown of HNF4A in HepG2 cells (36.6%) led to a significant decrease of UGT2B7 (19.8%) and higher cytotoxicity (p < 0.05). The overexpression of HNF4A in HepG2 cells (31.2%) led to a significant increase of UGT2B7 (24.4%) and improved cell viability (p < 0.05). Besides, HNF4A and UGT2B7 were both decreased in HepG2 cells and rats after treatment with emodin. In conclusion, emodin used long term or in high doses could inhibit the expression of HNF4A, thereby reducing the expression of UGT2B7 and causing hepatotoxicity.
NMDA receptor (NMDAR) antagonists such as ketamine, can reproduce many of the symptoms of schizophrenia. A reliable indicator of NMDAR channel blocker action in vivo is the augmentation of neuronal oscillation power. Since the coordinated and rhythmic activation of neuronal assemblies (oscillations) is necessary for perception, cognition and working memory, their disruption (inappropriate augmentation or inhibition of oscillatory power or inter-regional coherence) both in psychiatric conditions and with NMDAR antagonists may reflect the underlying defects causing schizophrenia symptoms. NMDAR antagonists and knockout (KO) mice were used to evaluate the role of GluN2C and GluN2D NMDAR subunits in generating NMDAR antagonist-induced oscillations. We find that basal oscillatory power was elevated in GluN2C-KO mice, especially in the low gamma frequencies while there was no statistically significant difference in basal oscillations between WT and GluN2D-KO mice. Compared to wildtype (WT) mice, NMDAR channel blockers caused a greater increase in oscillatory power in GluN2C-KO mice and were relatively ineffective in inducing oscillations in GluN2D-KO mice. In contrast, preferential blockade of GluN2A-and GluN2B-containing receptors induced oscillations that did not appear to be changed in either KO animal. We propose a model wherein NMDARs containing GluN2C in astrocytes and GluN2D in interneurons serve to detect local cortical
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