Biology subjects

Sawa, A.

Publications and source records attributed to Sawa, A..

4 recordsLinked to original sources

bioRxiv2018

Overlapping but asymmetrical relationships between schizophrenia and autism revealed by brain connectivity

(Abstract included 248 words)Although the relationship between schizophrenia spectrum disorder (SSD) and autism spectrum disorder (ASD) has long been debated, it has not yet been fully elucidated. To address this issue, we took advantage of dual (ASD and SSD) classifiers that discriminate patients from their controls based on resting state brain functional connectivity. An SSD classifier using sophisticated machine-learning algorithms that automatically selected SSD- specific functional connections was applied to Japanese datasets including adult patients with SSD in a chronic stage. We demonstrated good performance of the SSD classification for independent validation cohorts. The generalizability was tested by USA and European cohorts in a chronic stage, and one USA cohort including first episode schizophrenia. The specificity was tested by two adult Japanese cohorts of ASD and major depressive disorder, and one European cohort of attention-deficit hyperactivity disorder. The weighted linear summation of the classifiers functional connections constituted the biological dimensions representing neural liability to the disorders. Our previously developed robust ASD classifier constituted the ASD dimension. Distributions of individuals with SSD, ASD and healthy controls were examined on the SSD and ASD biological dimensions. The SSD and ASD populations exhibited overlapping but asymmetrical patterns on the two biological dimensions. That is, the SSD population showed increased liability on the ASD dimension, but not vice versa. Furthermore, the two dimensions were correlated within the ASD population but not the SSD population. Using the two biological dimensions based on resting-state functional connectivity enabled us to quantify and visualize the relationships between SSD and ASD.

neuroscience↗

bioRxiv2018

Glutathione shapes glutamatergic transmission

Glutamate is the most abundant excitatory neurotransmitter, present at the bulk of cortical synapses, and participating in many physiologic and pathologic processes ranging from learning and memory to stroke. The tripeptide, glutathione, is one third glutamate and present at up to low millimolar intracellular concentrations in brain, mediating antioxidant defenses and drug detoxification. Because of the substantial amounts of brain glutathione and its rapid turnover under homeostatic control, we hypothesized that glutathione is a relevant reservoir of glutamate, and could influence synaptic excitability. We find that drugs which inhibit generation of glutamate by the glutathione cycle elicit decreases in cytosolic glutamate and decreased miniature excitatory post synaptic potential (mEPSC) frequency. In contrast, pharmacologically decreasing the biosynthesis of glutathione leads to increases in cytosolic glutamate and enhanced mEPSC frequency. The glutathione cycle can compensate for decreased excitatory neurotransmission when the glutamate-glutamine shuttle is inhibited. Glutathione may be a physiologic reservoir of glutamate neurotransmitter.\n\nSignificanceGlutathione is the principal antioxidant and redox regulator in cells. In addition to its essential roles in redox homeostasis it functions as cofactors for a multitude of enzymes. We show here that glutathione is a reservoir for synaptic glutamate, the excitatory neurotransmitter in the central nervous system. Deficits in glutathione have been linked to multiple neurodegenerative and neuropsychiatric disorders. Accordingly, agents that restore glutathione-glutamate homeostasis may afford therapeutic benefit.

neuroscience↗

bioRxiv2018

PET Brain imaging of α7-nAChR with ASEM Reproducibility, occupancy, receptor density, and changes in schizophrenia

The 7 nicotinic acetylcholine receptor (nAChR) increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The a7-nAChR primarily is located in cerebral cortex and sub-cortical regions, compared to the 4{beta}2 nAChR subtype that has a more subcortical distribution. The highly cortical distribution suggests a role of a7-nAChR in cognition. We expanded the first-in-human PET imaging of 7-nAChR with [18F]ASEM from five to 21 healthy non-smoking volunteers and added preliminary evidence of binding in six male patients with schizophrenia. Study aims included 1) confirmation of test-retest reproducibility of [18F]ASEM binding in normal volunteers, 2) demonstration of specificity of [18F]ASEM binding by competition with DMXB-A, an 7-nAChR partial agonist previously tested in clinical trials of patients with schizophrenia, 3) estimation of [18F]ASEM binding potentials and 7-nAChR density in vivo in humans, and 4) 7-nAChR binding in patients with schizophrenia compared to healthy volunteers.\n\nTest-retest PET confirmed reproducibility (>90%) (variability [≤] 7%) of [18F]ASEM volume of distribution (VO_SCPLOWTC_SCPLOW) estimates in healthy volunteers. Repeated sessions of PET in five healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of 7-nAChR by DMXB-A at 17-49% for plasma concentrations at 60-200 nM DMXB-A. In agreement with evidence post-mortem, 7-nAChR density (Bmax) averaged 0.67-0.82 nM and inhibitor affinity constant (KO_SCPLOWIC_SCPLOW) averaged 170-385 nM. Median VO_SCPLOWTC_SCPLOW in a feasibility study of six patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus. Mann-Whitney test identified cingulate cortex and hippocampus as regions with significantly lower median VO_SCPLOWTC_SCPLOW in patients than in healthy volunteers when a single outlier patient was excluded from analysis (P = 0.02, corrected for multiple comparisons).

neuroscience↗

bioRxiv2017

Glutathione S-transferases: unexpected roles in astrocyte activation and astrocyte-microglia communication during brain inflammation

Astrocytes and microglia play critical roles in brain inflammation, but their mutual regulation is not fully understood. Here we report unexpected roles for glutathione S-transferases (GSTs), particularly GSTM1, in astrocyte activation and astrocyte-mediated enhancement of microglia activation during brain inflammation. We found that astrocyte-specific silencing of GSTM1 expression in the prefrontal cortex (PFC) attenuated microglia activation in brain inflammation induced by systemic injection of lipopolysaccharides (LPS). Gstm1 silencing in astrocytes also attenuated LPS-induced TNF- production by microglia in co-culture. In astrocytes, GSTM1 was required for the activation of nuclear factor-{kappa}B (NF-{kappa}B) and c-Jun N-terminal kinases (JNK) and the production of pro-inflammatory mediators previously implicated in microglia activation, such as granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) and chemokine (C-C motif) ligand 2 (CCL2). Similar results were also obtained with GSTT2 both in vitro and in vivo. Thus, our study identified a critical role for GSTs in priming astrocytes and enhancing microglia activation during brain inflammation.\n\nSignificant StatementAstrocytes and microglia play critical roles in brain inflammation, but it is not fully understood how astrocytes regulate microglia activation. Here we report a novel mechanism by which glutathione S-transferases (GSTs), the enzymes for phase II detoxification of xenobiotic metabolism, in astrocytes control microglia activation during brain inflammation. We found that GSTs, particularly GSTM1, regulate the induction of pro-inflammatory mediators via the activation of NF-{kappa}B and JNK in astrocytes. Our studies provide evidence that GST enzymes are active players in brain inflammation and can be targeted to regulate microglia activation.

immunology↗