Reciprocal differentiation via GABAergic components and ASD-related phenotypes in hES with 1q21.1 CNV

Copy number variations (CNVs) in the distal 1q21.1 region, both deletion (1q del) and duplication (1q dup), are associated with autism spectrum disorder, epilepsy and schizophrenia. Besides common phenotypes, 1q del and 1q dup manifest opposite clinical phenotypes?e.g., microcephaly in 1q del and macrocephaly in 1q dup. However, molecular and cellular mechanisms are still elusive. We generate isogenic human ES (hES) cell lines with reciprocal 1q21.1 CNVs using CRISPR/Cas9 system and differentiate them into 2-dimensional (2-D) neurons and 3-D cortical organoids. Our study recapitulates opposite organoid size and shows dosage-dependent differentiation changes i.e., more mature and GABAergic components in 1q del and more proliferative state in 1q dup. In contrast, both CNVs show hyperexcitability and altered expressions of glutamate system as common features. These results demonstrate that 1q21.1 CNVs dramatically affect cell fate in the early neurodevelopmental periods. This is the first isogenic model of hES CNVs and our findings provide new insights into the underlying mechanisms of neurodevelopmental disorders.

919 Syrup Alleviates Postpartum Depression by Modulating the Structure and Metabolism of Gut Microbes and Affecting the Function of the Hippocampal GABA/Glutamate System

Postpartum depression (PPD) is a mental disorder that affects pregnant women around the world, with serious consequences for mothers, families, and children. Its pathogenesis remains unclear, and medications for treating PPD that can be used during lactation remain to be identified. 919 syrup (919 TJ) is a Chinese herbal medicine that has been shown to be beneficial in the treatment of postpartum depression in both clinical and experimental studies. The mechanism of action of 919 TJ is unclear. 919 syrup is ingested orally, making the potential interaction between the drug and the gut microbiome impossible to ignore. We therefore hypothesized that 919 syrup could improve the symptoms of postpartum depression by affecting the structure and function of the intestinal flora, thereby altering hippocampal metabolism. We compared changes in hippocampal metabolism, fecal metabolism, and intestinal microflora of control BALB/c mice, mice with induced untreated PPD, and mice with induced PPD treated with 919 TJ, and found that 4-aminobutyric acid (GABA) in the hippocampus corresponded with PPD behaviors. Based on changes in GABA levels, multiple key gut bacterial species (Mucispirillum schaedleri, Bifidobacterium pseudolongum, Desulfovibrio piger, Alloprevotella tannerae, Bacteroides sp.2.1.33B and Prevotella sp. CAG:755) were associated with PPD. Metabolic markers that may represent the function of the intestinal microbiota in mice with PPD were identified (Met-Arg, urocanic acid, thioetheramide-PC, L-pipecolic acid, and linoleoyl ethanolamide). The relationship between these factors is not a simple one-to-one correspondence, but more likely a network of staggered functions. We therefore believe that the composition and function of the entire intestinal flora should be emphasized in research studying the gut and PPD, rather than changes in the abundance of individual bacterial species. The introduction of this concept of “GutBalance” may help clarify the relationship between gut bacteria and systemic disease.

Imaging Brain Glx Dynamics in Response to Pressure Pain Stimulation: A 1H-fMRS Study

Glutamate signalling is increasingly implicated across a range of psychiatric, neurological and pain disorders. Reliable methodologies are needed to probe the glutamate system and understand glutamate dynamics in vivo. Functional magnetic resonance spectroscopy (1H-fMRS) is a technique that allows measurement of glutamatergic metabolites over time in response to task conditions including painful stimuli. In this study, 18 healthy volunteers underwent 1H-fMRS during a pressure-pain paradigm (8 blocks of REST and 8 blocks of PAIN) across two separate sessions. During each session, estimates of glutamate + glutamine (Glx), scaled to total creatine (tCr = creatine + phosphocreatine) were determined for averaged REST and PAIN conditions within two separate regions of interest: the anterior cingulate cortex (ACC) and dorsal ACC (dACC). A two-way repeated measures analysis of variance determined a significant main effect of CONDITION (p = 0.025), with higher Glx/tCr during PAIN compared to REST across combined sessions, in the dACC ROI only. However, increases in dACC Glx/tCr during PAIN compared to REST showed limited reliability and reproducibility across sessions. Future test-retest 1H-fMRS studies should examine modified or alternative paradigms to determine more reliable methodologies to challenge the glutamate system that may then be applied in patient groups and experimental medicine studies.

Ketamine Alters Functional Gamma and Theta Resting-State Connectivity in Healthy Humans: Implications for Schizophrenia Treatment Targeting the Glutamate System

Disturbed functional connectivity is assumed to cause neurocognitive deficits in patients suffering from schizophrenia. A Glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction has been suggested as a possible mechanism underlying altered connectivity in schizophrenia, especially in the gamma- and theta-frequency range. The present study aimed to investigate the effects of the NMDAR-antagonist ketamine on resting-state power, functional connectivity, and schizophrenia-like psychopathological changes in healthy volunteers. In a placebo-controlled crossover design, 25 healthy subjects were recorded using resting-state 64-channel-electroencephalography (EEG) (eyes closed). The imaginary coherence-based Multivariate Interaction Measure (MIM) was used to measure gamma and theta connectivity across 80 cortical regions. The network-based statistic was applied to identify involved networks under ketamine. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). Ketamine caused an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01). Significant increases in resting-state gamma and theta power were observed under ketamine compared to placebo (p < 0.05). The source-space analysis revealed two distinct networks with an increased mean functional gamma- or theta-band connectivity during the ketamine session. The gamma-network consisted of midline regions, the cuneus, the precuneus, and the bilateral posterior cingulate cortices, while the theta-band network involved the Heschl gyrus, midline regions, the insula, and the middle cingulate cortex. The current source density (CSD) within the gamma-band correlated negatively with the PANSS negative symptom score, and the activity within the gamma-band network correlated negatively with the subjective changed meaning of percepts subscale of the 5D-ASC. These results are in line with resting-state patterns seen in people who have schizophrenia and argue for a crucial role of the glutamate system in mediating dysfunctional gamma- and theta-band-connectivity in schizophrenia. Resting-state networks could serve as biomarkers for the response to glutamatergic drugs or drug development efforts within the glutamate system.

Interactions of neuroimmune signaling and glutamate plasticity in addiction

Chronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe neuroimmune mechanisms that may be linked to aberrant glutamate signaling in addiction. We focus specifically on the nuclear factor-kappa B (NF-κB) pathway, a potentially important neuroimmune mechanism that may be a key player in driving drug-seeking behavior. We highlight the importance of astroglial-microglial crosstalk, and how this interacts with known glutamatergic dysregulations in addiction. Then, we describe the importance of studying non-neuronal cells with unprecedented precision because understanding structure-function relationships in these cells is critical in understanding their role in addiction neurobiology. Here we propose a working model of neuroimmune-glutamate interactions that underlie drug use motivation, which we argue may aid strategies for small molecule drug development to treat substance use disorders. Together, the synthesis of this review shows that interactions between glutamate and neuroimmune signaling may play an important and understudied role in addiction processes and may be critical in developing more efficacious pharmacotherapies to treat SUDs.

Characterization of fibers after xylanase and modified laccase-glutamate system biobleaching of old newsprint pulp

The macroscopic and microscopic properties of old newsprint pulp with xylanase, MLac/Glu (modified laccase-glutamate system), and X-MLac/Glu (xylanase synergistic modified laccase-glutamate system) pretreatment was investigated by means of fiber quality measurements (FQA), attenuated total reflectance-infrared spectroscopy (ATR-IR), headspace gas chromatography (HSGC), X-ray diffract ion method (XRD), Low-temperature nitrogen absorption and scanning electron microscopy (SEM). Results showed that, compare with the control pulp, the brightness and lightness ( L ∗ {L^{\ast }} ) of hydrogen peroxide bleached pulp after X-MLac/Glu pretreatment increased by 5.86 % ISO and 3.58 %, respectively. FQA analysis revealed that coarseness and fine fiber content increased slightly. The content of carboxyl groups and water retention value increased remarkably by 31.11 % and 39.22 %, respectively. The paper physical analysis showed that the paper strength properties have improved significantly. The crystallinity of cellulose decreased by 3.82 % due to X-MLac/Glu pretreatment. ATR-IR analysis indicated some non-cellulose components are removed. The BJH average pore size and BET specific surface area increased after enzyme pretreatment. The SEM analysis showed that through X-MLac/Glu treatment the fiber surface becomes rough and the connections between the fibers become tighter, more fibrils appeared.

Activity-Based Anorexia Dynamically Dysregulates the Glutamatergic Synapse in the Nucleus Accumbens of Female Adolescent Rats

Intense physical activity and dieting are core symptoms of anorexia nervosa (AN). Their combination evolves into compulsivity, leading the patient into an out-of-control spiral. AN patients exhibit an altered activation of nucleus accumbens (NAc), revealing a dysfunctional mesocorticolimbic reward circuitry in AN. Since evidence exists that a dysregulation of the glutamate system in the NAc influences reward and taking advantage of the activity-based anorexia (ABA) rat model, which closely mimics the hallmarks of AN, we investigated the involvement of the glutamatergic signaling in the NAc in this experimental model. We here demonstrate that food restriction causes hyperactive and compulsive behavior in rodents, inducing an escalation of physical activity, which results in dramatic weight loss. Analysis of the glutamate system revealed that, in the acute phase of the pathology, ABA rats increased the membrane expression of GluA1 AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits together with its scaffolding protein SAP97. Recovery of body weight reduced GluN2A/2B balance together with the expression of their specific scaffolding proteins, thus suggesting persistent maladaptive neurotransmission. Taken together, AMPA and NMDA (N-methyl-D-aspartate) receptor subunit reorganization may play a role in the motivational mechanisms underlying AN.