Glutamatergic Transmission Research Articles

Molecular basis of retinal remodeling in a zebrafish model of retinitis pigmentosa

A hallmark of inherited retinal degenerative diseases such as retinitis pigmentosa (RP) is progressive structural and functional remodeling of the remaining retinal cells as photoreceptors degenerate. Extensive remodeling of the retina stands as a barrier for the successful implementation of strategies to restore vision. To understand the molecular basis of remodeling, we performed analyses of single-cell transcriptome data from adult zebrafish retina of wild type AB strain (WT) and a P23H mutant rhodopsin transgenic model of RP with continuous degeneration and regeneration. Retinas from both female and male fish were pooled to generate each library, combining data from both sexes. We provide a benchmark atlas of retinal cell type transcriptomes in zebrafish and insight into how each retinal cell type is affected in the P23H model. Oxidative stress is found throughout the retina, with increases in reliance on oxidative metabolism and glycolysis in the affected rods as well as cones, bipolar cells, and retinal ganglion cells. There is also transcriptional evidence for widespread synaptic remodeling and enhancement of glutamatergic transmission in the inner retina. Notably, changes in circadian rhythm regulation are detected in cones, bipolar cells, and retinal pigmented epithelium. We also identify the transcriptomic signatures of retinal progenitor cells and newly formed rods essential for the regenerative process. This comprehensive transcriptomic analysis provides a molecular road map to understand how the retina remodels in the context of chronic retinal degeneration with ongoing regeneration.

Enhancement of the Evoked Excitatory Transmission in the Nucleus Tractus Solitarius Neurons after Sustained Hypoxia in Mice Depends on A2A Receptors

The first synapses of the afferents of peripheral chemoreceptors are located in the Nucleus Tractus Solitarius (NTS) and there is evidence that short-term sustained hypoxia (SH – 24 h, FiO2 0.1) facilitates glutamatergic transmission in NTS neurons of rats. Adenosine is an important neuromodulator of synaptic transmission and hypoxia contributes to increase its extracellular concentration. The A2A receptors mediate the excitatory actions of adenosine and are active players in the modulation of neuronal networks in the NTS. Herein, we used knockout mice for A2A receptors (A2AKO) and electrophysiological recordings of NTS neurons were performed to evaluate the contribution of these receptors in the changes in synaptic transmission in NTS neurons of mice submitted to SH. The membrane passive properties and excitability of NTS neurons were not affected by SH and were similar between A2AKO and wild-type mice. The overall amplitude of spontaneous glutamatergic currents in NTS neurons of A2AKO mice was lower than in Balb/c WT mice. SH increased the amplitude of evoked glutamatergic currents of NTS neurons from WT mice by a non-presynaptic mechanism, but this enhancement was not observed in NTS neurons of A2AKO mice. Under normoxia, the amplitude of evoked glutamatergic currents was similar between WT and A2AKO mice. The data indicate that A2A receptors (a) modulate spontaneous glutamatergic currents, (b) do not modulate the evoked glutamatergic transmission in the NTS neurons under control conditions, and (c) are required for the enhancement of glutamatergic transmission observed in the NTS neurons of mice submitted to SH.

Glutamate receptor genetic variants affected peripheral glutamatergic transmission and treatment induced improvement of Indian ADHD probands

Attention deficit hyperactivity disorder (ADHD), a childhood-onset neurobehavioral disorder, often perturbs scholastic achievement and peer-relationship. The pivotal role of glutamate (Glu) in learning and memory indicated an influence of Glu in ADHD, leading to the exploration of Glu in different brain regions of ADHD subjects. We for the first time analyzed GluR genetic variations, Glu levels, as well as expression of Glu receptors (GluR) in the peripheral blood of eastern Indian ADHD probands to find out the relevance of Glu in ADHD prognosis. After obtaining informed written consent for participation, peripheral blood was collected for analyzing the genetic variants, Glu level, and expression of target genes. Since ADHD probands are often treated with methylphenidate or atomoxetine for providing symptomatic remediation, we have also tested post-therapeutic improvement in the ADHD trait scores in the presence of different GluR genotypes. Two variants, GRM7 rs3749380 “T” and GRIA1 rs2195450 “C”, exhibited associations with ADHD (P ≤ 0.05). A few GluR genetic variants showed significant association with higher trait severity, low IQ, lower plasma Glu level, down-regulated GluR mRNA expression, and poor response to medications. This indicates that down-regulated glutamatergic system may have an effect on ADHD etiology and treatment efficacy warranting further in-depth investigation.

Sex-specific modulation of the medial prefrontal cortex by glutamatergic median raphe neurons.

A substantial proportion of raphe neurons are glutamatergic. However, little is known about how these glutamatergic neurons modulate the forebrain. We investigated how glutamatergic median raphe nucleus (MRN) input modulates the medial prefrontal cortex (mPFC), a critical component of fear circuitry. We show that vesicular glutamate transporter 3 (VGLUT3)-expressing MRN neurons activate VGLUT3- and somatostatin-expressing neurons in the mPFC. Consistent with this modulation of mPFC GABAergic neurons, activation of MRN (VGLUT3) neurons enhances GABAergic transmission in mPFC pyramidal neurons and attenuates fear memory in female but not male mice. Serotonin plays a key role in MRN (VGLUT3) neuron-mediated GABAergic plasticity in the mPFC. In agreement with these female-specific effects, we observed sex differences in glutamatergic transmission onto MRN (VGLUT3) neurons and in mPFC (VGLUT3) neuron-mediated dual release of glutamate and GABA. Our results demonstrate a cell type-specific modulation of the mPFC by MRN (VGLUT3) neurons and reveal a sex-specific role of this neuromodulation in mPFC synaptic plasticity.

CNSC-11. SEIZURE PRESENTATION IN IDH WT GLIOMA IS RELATED TO UPREGULATED SYNAPTIC SIGNALING AND IONIC TRANSPORT GENES

Abstract Isocitrate dehydrogenase wildtype (IDH WT) glioblastoma (GBM) is the most common malignant brain tumor in adults and is universally lethal. Seizures often occur as a presenting sign of tumor. Recent studies have implicated tumor-neuron communication facilitating synaptic remodeling and peritumoral circuit hyperactivity influencing tumor growth. We assessed the clinical and transcriptional effect of seizure presentation on GBM biology. 63 tumor samples were analyzed for clinical characteristics. Bulk RNA sequencing data was used to identify differentially expressed genes (DEGs), gene sets enrichment analysis (GSEA), and gene ontologies (GO). 24 IDH WT GBM patients presented with seizures compared to 39 patients presenting with other symptoms. There were no significant differences between age at presentation, sex, tumor lobe, tumor location, or grade of tumor. GSEA of gene ontologies revealed upregulated genes in the seizure cohort were largely related to synaptic signaling, ionic transport, and receptor signaling (p-val< 0.05). Alternatively downregulated gene sets were related to extracellular matrix organization, and inflammatory and immune response (p-val< 0.05). Focusing on significantly upregulated DEGs (padj< 0.05,) biological processes related to glutamatergic synaptic transmission and cellular components related to synaptic structures were upregulated. Alternatively, significantly downregulated DEGs (padj< 0.05) were related to biological processes of immunity and extracellular matrix organization and cellular components related to the extracellular matrix. Upregulated genes include IGFN1 and THBS4, both involved in synapse assembly, and SLC17A3, involved in presynaptic glutamate sorting (Log2FC >1,padj <0.05). The downregulated genes include numerous collagen related genes and immune related genes and KCNJ15, an inward rectifying potassium channel and GABRR1, a GABA-rho subunit. Using bulk RNA sequencing in a clinically similar set of IDH WT tumors, we found gene sets and gene ontologies related to synaptic signaling and glutamatergic signaling upregulated in patients with seizures while genes related to both extracellular matrix and immune inflammation were downregulated.

CNSC-14. T-TYPE CALCIUM CHANNELS REGULATE NEURON-GLIOBLASTOMA INTERACTIONS AND PROMOTE TUMOR GROWTH

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor with a dismal median survival of 15 months. Glioblastoma utilizes calcium signaling to regulate communication between tumor cells and the neuronal microenvironment. T-type calcium channels (TTCCs) are voltage gated calcium channels expressed in various types of neurons throughout the brain regulating glutamatergic synaptic transmission. We analyzed spatial transcriptomics of human GBM tumors and found that TTCCs are expressed in infiltrating tumor regions and enriched for neuronal development spatial patterns and exhibit neurodevelopmental signatures. Analysis of single cells transcriptomic of human GBM tumors demonstrated that TTCCs are enriched in neuronal subtypes. To complement publicly available data,we treated Glioblastoma Stem cells (GSCs) with an FDA-approved repurposed TTCC blocker, mibefradil, and found downregulation of genes associated with neuron processes such as synapse organization, postsynaptic density and glutamatergic synapses. Treatment of GSCs with mibefradil abrogated cell proliferation in the presence of glutamate. We examined the effects of neuronal Cav3.2 on GBM growth. Genetic Cav3.2 knockout (Cav3.2 KO) in the microenvironment of mice xenografted with syngeneic cell lines (GL261 and CT2A) exhibited significant tumor volume reduction as well as increased survival compared to WT mice in both cell lines. Cav3.2 KO tumors exhibited a decrease in proliferation (Ki67+) and neuronal connections (VGlut1) measured by immunofluorescence compared to WT mice. Cav3.2KO neuron-GBM co-cultures exhibited a significant decrease in proliferation compared to WT neuron-GBM co-cultures. Cav3.2KO neuron-GBM co-cultures exhibited a decrease in synaptic connections and a decrease in neuronal projections to GBM cells compared to WT neuron-GBM co-cultures. Transcriptomic analysis of tumors from Cav3.2KO tumors revealed deregulation of genes associated synaptic transmission, glutamatergic synapses and postsynaptic specialization. Altogether, our findings indicate a role of Cav3.2 in regulating tumors and neurons and promoting GBM progression.

Effects of propofol on presynaptic synapsin phosphorylation in the mouse brain in vivo

The commonly used general anesthetic propofol can enhance the γ-aminobutyric acid-mediated inhibitory synaptic transmission and depress the glutamatergic excitatory synaptic transmission to achieve general anesthesia and other outcomes. In addition to the actions at postsynaptic sites, the modulation of presynaptic activity by propofol is thought to contribute to neurophysiological effects of the anesthetic, although potential targets of propofol within presynaptic nerve terminals are incompletely studied at present. In this study, we explored the possible linkage of propofol to synapsins, a family of neuron-specific phosphoproteins which are the most abundant proteins on presynaptic vesicles, in the adult mouse brain in vivo. We found that an intraperitoneal injection of propofol at a dose that caused loss of righting reflex increased basal levels of synapsin phosphorylation at the major representative phosphorylation sites (serine 9, serine 62/67, and serine 603) in the prefrontal cortex (PFC) of male and female mice. Propofol also elevated synapsin phosphorylation at these sites in the striatum and S9 and S62/67 phosphorylation in the hippocampus, while propofol had no effect on tyrosine hydroxylase phosphorylation in striatal nerve terminals. Total synapsin protein expression in the PFC, hippocampus, and striatum was not altered by propofol. These results reveal that synapsin could be a novel substrate of propofol in the presynaptic neurotransmitter release machinery. Propofol possesses the ability to upregulate synapsin phosphorylation in broad mouse brain regions.

Anterior and Posterior Basolateral Amygdala Projections of Cell Type–Specific D1-Expressing Neurons From the Medial Prefrontal Cortex Differentially Control Alcohol-Seeking Behavior

BackgroundAlcohol use disorder is characterized by compulsive alcohol-seeking behavior, which is associated with dysregulation of afferent projections from the medial prefrontal cortex to the basolateral amygdala (BLA). However, the contribution of the cell type–specific mechanism in this neuronal circuit to alcohol-seeking behavior remains unclear. MethodsMice were trained with 2-bottle choice and operant alcohol self-administration procedures. Anterograde and retrograde viral methods traced the connection between dopamine type 1 receptor (D1R) neurons and BLA neurons. Electrophysiology and in vivo optogenetic techniques were used to test the function of neural circuits in alcohol-seeking behavior. ResultsChronic alcohol consumption preferentially changed the activity of posterior BLA (pBLA) neurons but not anterior BLA (aBLA) neurons and overexcited D1R neurons in the medial prefrontal cortex. Interestingly, we found that 2 populations of D1R neurons, anterior and posterior (pD1R) neurons, separately targeted the aBLA and pBLA, respectively, and only a few D1R neurons innervated both aBLA and pBLA neurons. Furthermore, pD1R neurons exhibited more excitability than anterior D1R neurons in alcohol-drinking mice. Moreover, we observed enhanced glutamatergic transmission and an increased NMDA/AMPA receptor ratio in the medial prefrontal cortex inputs from pD1R neurons to the pBLA. Optogenetic long-term depression induction of the pD1R-pBLA circuit reduced alcohol-seeking behavior, while optogenetic long-term depression or long-term potentiation induction of the anterior D1R–aBLA circuit produced no change in alcohol intake. ConclusionsThe pD1R-pBLA circuit mediates chronic alcohol consumption, which may suggest a cell type–specific neuronal mechanism underlying reward-seeking behavior in alcohol use disorder.

Glutamate secretion by embryonic stem cells as an autocrine signal to promote proliferation

Glutamate, the major excitatory neurotransmitter in the central nervous system, has also been found to play a role in embryonic stem (ES) cells. However, the exact mechanism and function of glutamatergic signaling in ES cells remain poorly understood. In this study, we identified a glutamatergic transmission circuit in ES cells that operates through an autocrine mechanism and regulates cell proliferation. We performed biological analyses to identify the key components involved in glutamate biosynthesis, packaging for secretion, reaction, and reuptake in ES cells, including glutaminase, vesicular glutamate transporter, glutamate N-methyl-d-aspartate (NMDA) receptor, and cell membrane excitatory amino-acid transporter (EAAT). We directly quantified the released glutamate signal using microdialysis-high performance liquid chromatography-tandem mass spectrometry (MD–HPLC–MS–MS). Pharmacological inhibition of endogenous glutamate release and the resulting tonic activation of NMDA receptors significantly affected ES cell proliferation, suggesting that ES cells establish a glutamatergic autocrine niche via releasing and responding to the transmitter for their own regulation.

5-HT6 Receptors Control GABAergic Transmission and CA1 Pyramidal Cell Output of Dorsal Hippocampus.

The blockade of 5-HT6 receptors represents an experimental approach that might ameliorate the memory deficits associated with brain disorders, including Alzheimer's disease and schizophrenia. However, the synaptic mechanism by which 5-HT6 receptors control the GABAergic and glutamatergic synaptic transmission is barely understood. In this study, we demonstrate that pharmacological manipulation of 5-HT6 receptors with the specific agonist EMD 386088 (7.4nM) or the antagonist SB-399885 (300nM) modulates the field inhibitory postsynaptic potentials of the dorsal hippocampus and controls the strength of the population spike of pyramidal cells. Likewise, pharmacological modulation of 5-HT6 controls the magnitude of paired-pulse inhibition, a phenomenon mediated by GABAergic interneurons acting via GABAA receptors of pyramidal cells. The effects of pharmacological manipulation of the 5-HT6 receptor were limited to GABAergic transmission and did not affect the strength of field excitatory postsynaptic potentials mediated by the Schaffer collaterals axons. Lastly, in a modified version of the Pavlovian autoshaping task that requires the activation of the hippocampal formation, we demonstrated that the anti-amnesic effect induced by the blockade of the 5-HT6 receptor is prevented when the GAT1 transporter is blocked, suggesting that modulation of GABAergic transmission is required for the anti-amnesic properties of 5-HT6 receptor antagonists.

The opioid peptide met-enkephalin modulates thalamo-cortical excitation inhibition balance in a medial thalamus-anterior cingulate cortex circuit

Activation of opioid receptors in the anterior cingulate cortex (ACC) mediates aspects of analgesia induced by both exogenous and endogenous opioids. We have previously shown that opioid signaling disrupts both afferent excitatory and indirect inhibitory synaptic transmission from the medial thalamus (MThal) to the ACC, but the effects of non-selective opioid peptides such as [Met]5-enkephalin (ME) within this circuit remain poorly understood. The goal of the current study was to understand how ME modulates thalamic-driven excitatory and inhibitory synaptic transmission onto layer V pyramidal neurons in the ACC. We used pharmacology, brain slice electrophysiology and optogenetic stimulation to study opioid-mediated modulation of optically evoked glutamatergic and GABAergic transmission. The results revealed that bath perfused ME inhibited both AMPA-mediated excitatory and GABA-mediated inhibitory synaptic transmission in the ACC. However, inhibitory transmission was more potently inhibited than excitatory transmission by ME. This preferential reduction in GABAA-mediated synaptic transmission was primarily due to the activation of delta opioid receptors by ME and resulted in a net disinhibition of MThal-ACC excitatory pathway. These results suggest that moderate concentrations of ME can lead to a net increase in excitatory drive of ACC circuitry and that analgesia may be associated with disinhibition rather than inhibition of ACC subcircuits.

Integrin α3 is required for high-frequency repetitive transcranial magnetic stimulation-induced glutamatergic synaptic transmission in mice with ischemia.

Repetitive transcranial magnetic stimulation (rTMS) is an effective therapy in post-stroke motor recovery. However, the underlying mechanisms of rTMS regulates long-lasting changes with synaptic transmission and glutamate receptors function (including AMPARs or NMDARs) remains unclear. Mice were received 10-Hz rTMS treatment once daily on the third day after photothrombotic (PT) stroke for 18 days. Motor behaviors and the Western blot were used to evaluate the therapeutic efficacy of 10-Hz rTMS in the mice with PT model. Moreover, we used wild-type (WT) and NEX-α3-/- mice to further explore the 10-Hz rTMS effect. We found that 10-Hz rTMS improved the post-stroke motor performance in the PT mice. Moreover, the levels of AMPAR, vGlut1, and integrin α3 in the peri-infarct were significantly increased in the rTMS group. In contrast, 10-Hz rTMS did not induce these aforementioned effects in NEX-α3-/- mice. The amplitude of AMPAR-mediated miniature excitatory postsynaptic currents (EPSCs) and evoked EPSCs was increased in the WT + rTMS group, but did not change in NEX-α3-/- mice with rTMS. In this study, 10-Hz rTMS improved the glutamatergic synaptic transmission in the peri-infract cortex through effects on integrin α3 and AMPARs, which resulted in motor function recovery after stroke.

The effects of Phycocyanobilin on experimental arthritis involve the reduction in nociception and synovial neutrophil infiltration, inhibition of cytokine production, and modulation of the neuronal proteome.

The antinociceptive and pharmacological activities of C-Phycocyanin (C-PC) and Phycocyanobilin (PCB) in the context of inflammatory arthritis remain unexplored so far. In the present study, we aimed to assess the protective actions of these compounds in an experimental mice model that replicates key aspects of human rheumatoid arthritis. Antigen-induced arthritis (AIA) was established by intradermal injection of methylated bovine serum albumin in C57BL/6 mice, and one hour before the antigen challenge, either C-PC (2, 4, or 8 mg/kg) or PCB (0.1 or 1 mg/kg) were administered intraperitoneally. Proteome profiling was also conducted on glutamate-exposed SH-SY5Y neuronal cells to evaluate the PCB impact on this key signaling pathway associated with nociceptive neuronal sensitization. C-PC and PCB notably ameliorated hypernociception, synovial neutrophil infiltration, myeloperoxidase activity, and the periarticular cytokine concentration of IFN-γ, TNF-α, IL-17A, and IL-4 dose-dependently in AIA mice. In addition, 1 mg/kg PCB downregulated the gene expression for T-bet, RORγ, and IFN-γ in the popliteal lymph nodes, accompanied by a significant reduction in the pathological arthritic index of AIA mice. Noteworthy, neuronal proteome analysis revealed that PCB modulated biological processes such as pain, inflammation, and glutamatergic transmission, all of which are involved in arthritic pathology. These findings demonstrate the remarkable efficacy of PCB in alleviating the nociception and inflammation in the AIA mice model and shed new light on mechanisms underlying the PCB modulation of the neuronal proteome. This research work opens a new avenue to explore the translational potential of PCB in developing a therapeutic strategy for inflammation and pain in rheumatoid arthritis.

Graphene Oxide Nanosheets Hamper Glutamate Mediated Excitotoxicity and Protect Neuronal Survival In An In vitro Stroke Model.

Small graphene oxide (s-GO) nanosheets reversibly downregulate central nervous system (CNS) excitatory synapses, with potential developments as future therapeutic tools to treat neuro-disorders characterized by altered glutamatergic transmission. Excitotoxicity, namely cell death triggered by exceeding ambient glutamate fueling over-activation of excitatory synapses, is a pathogenic mechanism shared by several neural diseases, from ischemic stroke to neurodegenerative disorders. In this work, CNS cultures were exposed to oxygen-glucose deprivation (OGD) to mimic ischemic stroke in vitro, and it is show that the delivery of s-GO following OGD, during the endogenous build-up of secondary damage and excitotoxicity, improved neuronal survival. In a different paradigm, excitotoxicity cell damage was reproduced through exogenous glutamate application, and s-GO co-treatment protected neuronal integrity, potentially by directly downregulating the synaptic over-activation brought about by exogenous glutamate. This proof-of-concept study suggests that s-GO may find novel applications in therapeutic developments for treating excitotoxicity-driven neural cell death.

The Importance of α-Klotho in Depression and Cognitive Impairment and Its Connection to Glutamate Neurotransmission-An Up-to-Date Review.

Depression is a serious neuropsychiatric disease affecting an increasing number of people worldwide. Cognitive deficits (including inattention, poor memory, and decision-making difficulties) are common in the clinical picture of depression. Cognitive impairment has been hypothesized to be one of the most important components of major depressive disorder (MDD; referred to as clinical depression), although typical cognitive symptoms are less frequent in people with depression than in people with schizophrenia or bipolar disorder (BD; sometimes referred to as manic-depressive disorder). The importance of α-Klotho in the aging process has been well-documented. Growing evidence points to the role of α-Klotho in regulating other biological functions, including responses to oxidative stress and the modulation of synaptic plasticity. It has been proven that a Klotho deficit may contribute to the development of various nervous system pathologies, such as behavioral disorders or neurodegeneration. Given the growing evidence of the role of α-Klotho in depression and cognitive impairment, it is assumed that this protein may be a molecular link between them. Here, we provide a research review of the role of α-Klotho in depression and cognitive impairment. Furthermore, we propose potential mechanisms (related to oxidative stress and glutamatergic transmission) that may be important in α-Klotho-mediated regulation of mental and cognitive function.

Impact and Role of Hypothalamic Corticotropin Releasing Hormone Neurons in Withdrawal from Chronic Alcohol Consumption in Female and Male Mice.

Worldwide, alcohol use and abuse are a leading risk of mortality, causing 5.3% of all deaths (World Health Organization, 2022). The endocrine stress system, initiated by the peripheral release of corticotropin releasing hormone (CRH) from primarily glutamatergic neurons in the paraventricular nucleus of the hypothalamus (PVN), is profoundly linked with alcohol use, abuse, and relapse (Blaine and Sinha, 2017). These PVN CRH-releasing (PVNCRH) neurons are essential for peripheral and central stress responses (Rasiah et al., 2023), but little is known about how alcohol affects these neurons. Here, we show that two-bottle choice alcohol consumption blunts the endocrine-mediated corticosterone response to stress during acute withdrawal in female mice. Conversely, using slice electrophysiology, we demonstrate that acute withdrawal engenders a hyperexcitable phenotype of PVNCRH neurons in females that is accompanied by increased glutamatergic transmission in both male and female mice. GABAergic synaptic transmission was unaffected by alcohol history. We then tested whether chemogenetic inhibition of PVNCRH neurons would restore stress response in female mice with a history of alcohol drinking in the looming disk test, which mimics an approaching predator threat. Accordingly, inhibition of PVNCRH neurons reduced active escape in hM4Di alcohol history mice only. This study indicates that stress-responsive PVNCRH neurons in females are particularly affected by a history of alcohol consumption. Interestingly, women have indicated an increase in heavy alcohol use to cope with stress (Rodriguez et al., 2020), perhaps pointing to a potential underlying mechanism in alcohol-mediated changes to PVNCRH neurons that alter stress response.SIGNIFICANCE STATEMENT Paraventricular nucleus of the hypothalamus neurons that release corticotropin releasing hormone (PVNCRH) are vital for stress response. These neurons have been understudied in relation to alcohol and withdrawal despite profound relations between stress, alcohol use disorders (AUD), and relapse. In this study, we use a variety of techniques to show that acute withdrawal from a history of alcohol impacts peripheral stress response, PVNCRH neurons, and behavior. Specifically, PVNCRH are in a hyperactive state during withdrawal, which drives an increase in active stress coping behaviors in female mice only. Understanding how alcohol use and withdrawal affects stress responding PVNCRH neurons may contribute to finding new potential targets for the treatment of alcohol use disorder.

1H-MRS neurometabolite profiles and motor development in school-aged children who are HIV-exposed uninfected: a birth cohort study.

Alterations in regional neurometabolite levels as well as impaired neurodevelopmental outcomes have previously been observed in children who are HIV-exposed uninfected (CHEU). However, little is known about how neurometabolite profiles may relate to their developmental impairment. This study aimed to compare neurometabolite concentrations in school-aged CHEU and children who are HIV-unexposed (CHU) and to explore associations of neurometabolite profiles with functional neurodevelopment in the context of perinatal HIV exposure. We used 3 T single voxel proton magnetic resonance spectroscopy (1H-MRS) to quantify absolute and relative neurometabolites in the parietal gray and parietal white matter in school-aged CHEU and aged- and community-matched CHU. Functional neurodevelopmental outcomes were assessed using the early learning outcome measure (ELOM) tool at 6 years of age. Our study included 152 school-aged children (50% males), 110 CHEU and 42 CHU, with an average age of 74 months at the neuroimaging visit. In an adjusted multiple linear regression analysis, significantly lower glutamate (Glu) concentrations were found in CHEU as compared to CHU in the parietal gray matter (absolute Glu, p = 0.046; Glu/total creatine (Cr+PCr) ratios, p = 0.035) and lower total choline to creatine ratios (GPC+PCh/Cr+PCr) in the parietal white matter (p = 0.039). Using factor analysis and adjusted logistic regression analysis, a parietal gray matter Glu and myo-inositol (Ins) dominated factor was associated with HIV exposure status in both unadjusted (OR 0.55, 95% CI 0.17-0.45, p = 0.013) and adjusted analyses (OR 0.59, 95% CI 0.35-0.94, p = 0.031). With Ins as one of the dominating metabolites, this neurometabolic factor was similar to that found at the age of two years. Furthermore, this factor was also found to be correlated with ELOM scores of gross motor development in CHEU (Pearson's r = -0.48, p = 0.044). In addition, in CHEU, there was a significant association between Ins/Cr+PCr ratios in the parietal white matter and ELOM scores of fine motor coordination and visual motor integration in CHEU (Pearson's r = 0.51, p = 0.032). Reduced Glu concentrations in the parietal gray matter may suggest regional alterations in excitatory glutamatergic transmission pathways in the context of perinatal HIV and/or antiretroviral therapy (ART) exposure, while reduced Cho ratios in the parietal white matter suggest regional myelin loss. Identified associations between neurometabolite profiles and gross and fine motor developmental outcomes in CHEU are suggestive of a neurometabolic mechanism that may underlie impaired motor neurodevelopmental outcomes observed in CHEU.

Effects of NMDA-receptor blockade by ketamine on mentalizing and its neural correlates in humans: a randomized control trial

Schizophrenia is associated with various deficits in social cognition that remain relatively unaltered by antipsychotic treatment. While faulty glutamate signaling has been associated with general cognitive deficits as well as negative symptoms of schizophrenia, no direct link between manipulation of glutamate signaling and deficits in mentalizing has been demonstrated thus far. Here, we experimentally investigated whether ketamine, an uncompetitive N-methyl-D-aspartate receptor antagonist known to induce psychotomimetic effects, influences mentalizing and its neural correlates. In a randomized, placebo-controlled between-subjects experiment, we intravenously administered ketamine or placebo to healthy participants performing a video-based social cognition task during functional magnetic resonance imaging. Psychotomimetic effects of ketamine were assessed using the Positive and Negative Syndrome Scale. Compared to placebo, ketamine led to significantly more psychotic symptoms and reduced mentalizing performance (more “no mentalizing” errors). Ketamine also influenced blood oxygen level dependent (BOLD) response during mentalizing compared to placebo. Specifically, ketamine increased BOLD in right posterior superior temporal sulcus (pSTS) and increased connectivity between pSTS and anterior precuneus. These increases may reflect a dysfunctional shift of attention induced by ketamine that leads to mentalizing deficits. Our findings show that a psychotomimetic dose of ketamine impairs mentalizing and influences its neural correlates, a result compatible with the notion that deficient glutamate signaling may contribute to deficits in mentalizing in schizophrenia. The results also support efforts to seek novel psychopharmacological treatments for psychosis and schizophrenia targeting glutamatergic transmission.

The Role of the Adrenal-Gut-Brain Axis on Comorbid Depressive Disorder Development in Diabetes.

Diabetic patients are more affected by depression than non-diabetics, and this is related to greater treatment resistance and associated with poorer outcomes. This increase in the prevalence of depression in diabetics is also related to hyperglycemia and hypercortisolism. In diabetics, the hyperactivity of the HPA axis occurs in parallel to gut dysbiosis, weakness of the intestinal permeability barrier, and high bacterial-product translocation into the bloodstream. Diabetes also induces an increase in the permeability of the blood-brain barrier (BBB) and Toll-like receptor 4 (TLR4) expression in the hippocampus. Furthermore, lipopolysaccharide (LPS)-induced depression behaviors and neuroinflammation are exacerbated in diabetic mice. In this context, we propose here that hypercortisolism, in association with gut dysbiosis, leads to an exacerbation of hippocampal neuroinflammation, glutamatergic transmission, and neuronal apoptosis, leading to the development and aggravation of depression and to resistance to treatment of this mood disorder in diabetic patients.

Chronic treatment with D2-antagonist haloperidol leads to inhibitory/excitatory imbalance in striatal D1-neurons

Striatal dysfunction has been implicated in the pathophysiology of schizophrenia, a disorder characterized by positive symptoms such as hallucinations and delusions. Haloperidol is a typical antipsychotic medication used in the treatment of schizophrenia that is known to antagonize dopamine D2 receptors, which are abundantly expressed in the striatum. However, haloperidol’s delayed therapeutic effect also suggests a mechanism of action that may go beyond the acute blocking of D2 receptors. Here, we performed proteomic analysis of striatum brain tissue and found more than 400 proteins significantly altered after 30 days of chronic haloperidol treatment in mice, namely proteins involved in glutamatergic and GABAergic synaptic transmission. Cell-type specific electrophysiological recordings further revealed that haloperidol not only reduces the excitability of striatal medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) but also affects D1-MSNs by increasing the ratio of inhibitory/excitatory synaptic transmission (I/E ratio) specifically onto D1-MSNs but not D2-MSNs. Therefore, we propose the slow remodeling of D1-MSNs as a mechanism mediating the delayed therapeutic effect of haloperidol over striatum circuits. Understanding how haloperidol exactly contributes to treating schizophrenia symptoms may help to improve therapeutic outcomes and elucidate the molecular underpinnings of this disorder.