Glutamatergic Neurotransmission Research Articles

Sexual dimorphism, altered hippocampal glutamatergic neurotransmission, and cognitive impairment in APP knock-in mice.

It is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimer's disease (AD) progression, contributing to negative cognitive outcomes. In this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APPNL-F/NL--F). At 2-4 and 18+ months old, male and female APPNL/NL, APPNL-F/NL-F, and C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR). Then, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus using a glutamate-selective microelectrode in anesthetized mice. Glutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APPNL-F/NL-F male mice that declined with age compared to age-matched control mice. Young female APPNL-F/NL-F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APPNL-F/NL-F mice exhibited decreased CA1 basal glutamate levels, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APPNL-F/NL-F mice, but only aged females displayed recognition memory deficits compared to age-matched control mice. These findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APPNL-F/NL-F mice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL-F/NL-F mice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes.

Sex-Specific Impacts of Early Life Sleep Disruption: Ethanol Seeking, Social Interaction, and Anxiety Are Differentially Altered in Adolescent Prairie Voles.

Early life sleep is important for neuronal development. Using the highly social prairie vole rodent model, we have previously reported that early life sleep disruption (ELSD) during the preweaning period results in interference with social bonding and increases ethanol consumption following a stressor in adulthood. Furthermore, ELSD increases parvalbumin expression and reduces glutamatergic neurotransmission in cortical regions in adult prairie voles. To understand the impact of ELSD on the lifespan, an examination of an earlier time in life is necessary. The aim of the present study was to examine behavioral outcomes of ELSD on adolescent prairie voles. Given the known effects of ELSD on development of neuronal systems involved in mood and social motivation, we hypothesized that anxiety, risk, and reward-related behaviors would be impacted by ELSD in adolescent prairie voles. We report that both male and female adolescent prairie voles that experienced ELSD showed heightened anxiety-like behavior compared to age-matched controls (CONs) as measured by a light-dark box. Additionally, both male and female ELSD voles showed reductions in both ethanol preference and consumption, and affiliative behavior compared to CONs. These results suggest that adolescent prairie voles of both sexes experience heightened anxiety-like behavior and reduced reward-seeking behaviors after ELSD. These results further suggest that early life sleep is critically important for neurotypical behaviors in adolescence.

Dysregulated balance of D- and L-amino acids modulating glutamatergic neurotransmission in severe spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to motor neuron survival, SMN deficiency affects the integrity and function of afferent synapses that provide glutamatergic excitatory drive essential for motor neuron firing and muscle contraction. However, it is unknown whether deficits in the metabolism of excitatory amino acids and their precursors contribute to neuronal dysfunction in SMA. To address this issue, we measured the levels of the main neuroactive D- and L-amino acids acting on glutamatergic receptors in the central nervous system of SMNΔ7 mice as well as the cerebrospinal fluid (CSF) of SMA patients of varying severity before and after treatment with the SMN-inducing drug Nusinersen. Our findings reveal that SMN deficiency disrupts glutamate and serine metabolism in the CSF of severe SMA patients, including decreased concentration of L-glutamate, which is partially corrected by Nusinersen therapy. Moreover, we identify dysregulated L-glutamine to L-glutamate conversion as a shared neurochemical signature of altered glutamatergic synapse metabolism that implicates astrocyte dysfunction in both severe SMA patients and mouse models. Lastly, consistent with a correlation of higher CSF levels of D-serine with better motor function in severe SMA patients, we show that daily supplementation with the NMDA receptor co-agonist D-serine improves neurological deficits in SMNΔ7 mice. Altogether, these findings provide direct evidence for dysregulation of D- and L-amino acid metabolism linked to glutamatergic neurotransmission in severe SMA and have potential implications for treating this neurological disorder.

Local activity alterations in autism spectrum disorder correlate with neurotransmitter properties and ketamine induced brain changes.

Local activity alterations in ASD co-localize with glutamatergic and GABAergic neurotransmission and were similar to ketamine-induced brain changes.

Activation of ionotropic and group I metabotropic glutamate receptors stimulates kisspeptin neuron activity in mice.

Different populations of hypothalamic kisspeptin (KISS1) neurons located in the rostral periventricular area of the third ventricle (RP3V) and arcuate nucleus (ARC) are thought to generate the sex-specific patterns of gonadotropin secretion. These neuronal populations integrate gonadal sex steroid feedback with internal and external cues relayed via the actions of neurotransmitters and neuropeptides. The excitatory amino acid neurotransmitter glutamate, the main excitatory neurotransmitter in the brain, plays a role in regulating gonadotropin secretion, at least partially through engaging KISS1 signaling. The expression and function of individual glutamate receptor subtypes in KISS1 neurons, however, are not well characterized. Here, we used GCaMP-based calcium imaging and patch-clamp electrophysiology to assess the impact of activating individual ionotropic (iGluR) and group I metabotropic (mGluR) glutamate receptors on KISS1 neuron activity in the mouse RP3V and ARC. Our results indicate that activation of all iGluR subtypes and of group I mGluRs, likely mGluR1, consistently drives activity in the majority of KISS1 neurons within the RP3V and ARC of males and females. Our results also revealed, somewhat unexpectedly, sex- and region-specific differences. Indeed, activating (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type iGluRs evoked larger responses in female ARCKISS1 neurons than in their male counterparts whereas activating group I mGluRs induced larger responses in RP3VKISS1 neurons than in ARCKISS1 neurons in females. Together, our findings suggest that glutamatergic neurotransmission in KISS1 neurons, and its impact on the activity of these cells, might be sex- and region-dependent in mice.

Psilocybin and the glutamatergic pathway: implications for the treatment of neuropsychiatric diseases.

In recent decades, psilocybin has gained attention as a potential drug for several mental disorders. Clinical and preclinical studies have provided evidence that psilocybin can be used as a fast-acting antidepressant. However, the exact mechanisms of action of psilocybin have not been clearly defined. Data show that psilocybin as an agonist of 5-HT2A receptors located in cortical pyramidal cells exerted a significant effect on glutamate (GLU) extracellular levels in both the frontal cortex and hippocampus. Increased GLU release from pyramidal cells in the prefrontal cortex results in increased activity of γ-aminobutyric acid (GABA)ergic interneurons and, consequently, increased release of the GABA neurotransmitter. It seems that this mechanism appears to promote the antidepressant effects of psilocybin. By interacting with the glutamatergic pathway, psilocybin seems to participate also in the process of neuroplasticity. Therefore, the aim of this mini-review is to discuss the available literature data indicating the impact of psilocybin on glutamatergic neurotransmission and its therapeutic effects in the treatment of depression and other diseases of the nervous system.

Cofilin linked to GluN2B subunits of NMDA receptors is required for behavioral sensitization by changing the dendritic spines of neurons in the caudate and putamen after repeated nicotine exposure

BackgroundNicotine dependence is associated with glutamatergic neurotransmission in the caudate and putamen (CPu) of the forebrain which includes alterations in the structure of dendritic spines at glutamate synapses. These changes after nicotine exposure can lead to the development of habitual behaviors such as smoking. The present study investigated the hypothesis that cofilin, an actin-binding protein that is linked to the GluN2B subunits of N-methyl-D-aspartate (NMDA) receptors regulates the morphology of dendritic spines in the neurons of the CPu after repeated exposure to nicotine.ResultsAdult male rats received subcutaneous injections of nicotine (0.3 mg/kg/day) or vehicle for seven consecutive days. DiI staining was conducted to observe changes in dendritic spine morphology. Repeated subcutaneous injections of nicotine decreased the phosphorylation of cofilin while increasing the formation of thin spines and filopodia in the dendrites of medium spiny neurons (MSN) in the CPu of rats. Bilateral intra-CPu infusion of the cofilin inhibitor, cytochalasin D (12.5 µg/µL/side), restored the thin spines and filopodia from mushroom types after repeated exposure to nicotine. Similar results were obtained from the bilateral intra-CPu infusion of the selective GluN2B subunit antagonist, Ro 25-6981 (4 µM/µL/side). Bilateral intra-CPu infusion of cytochalasin D that interferes with the actin-cofilin interaction attenuated the repeated nicotine-induced increase in locomotor sensitization in rats.ConclusionsThese findings suggest that active cofilin alters the structure of spine heads from mushroom to thin spine/filopodia by potentiating actin turnover, contributing to behavioral sensitization after nicotine exposure.

Elevated peripheral glutamate and upregulated expression of NMDA receptor NR1 subunit in insomnia disorder.

The present study explored the serum glutamate (Glu), glutamine (Gln), glutamic acid dehydrogenase (GAD) concentrations and the mRNA expression levels of the N-methyl-D-aspartate receptor (NMDAR) NR1 subunit in the peripheral blood of patients with insomnia disorder (ID). To our knowledge, this is the first study showing an increase in the mRNA expression levels of the NMDAR NR1 subunit in patients with ID. This study included 30 ID patients and 30 matched healthy controls. We investigated the demographic and illness information and assessed subjective sleep quality using the Pittsburgh Sleep Quality Index. The Hamilton Depression Scale-17 and Hamilton Anxiety Scale were used to evaluate the patients' symptoms of depression and anxiety, respectively. The quantifications of Glu, Gln and GAD concentrations were performed by Enzyme-linked immunosorbent assay (ELISA). Real-time PCR was used to detect the mRNA expression levels of the NMDAR NR1 subunit in peripheral blood. Compared with the healthy control group, the serum Glu concentrations and the mRNA expression levels of the NMDAR NR1 subunit in the ID group were significantly higher. However, there was no significant difference in Gln and GAD between the two groups. The receiver operating characteristic (ROC) analysis showed that the mRNA expression levels of the NMDAR NR1 subunit could distinguish ID patients from healthy individuals (area under the curve: 0.758; sensitivity: 73.3%; specificity: 76.7%). A negative correlation was found between the mRNA expression levels of the NMDAR NR1 subunit for age, total duration of illness, and age of first onset in the ID group, whereas a positive correlation was detected for daytime dysfunction. Glutamatergic neurotransmission was abnormal in ID patients. Additionally, the mRNA expression levels of the NMDAR NR1 subunit appeared to have potential as a clinical biomarker for ID. However, the sample size of our study was limited, and future studies with larger sample sizes are needed to further validate and explore the mechanisms involved and to assess the reliability of the biomarker.

8372 Evidence of dACC Glutamate Modulation During Top-down Inhibitory Control Predicting Weight Loss Ability in Individuals with Obesity Using1H fMRS

Abstract Disclosure: J.M. Eichstaedt: None. R. Sochocki: None. D. Khatib: None. N. Miller: None. V.A. Diwadkar: None. P. Burghardt: None. A.E. Rothberg: None. J.A. Stanley: None. Poor weight loss maintenance (WLM) following dietary intervention has been associated with poor top-down inhibitory control. The neurobiological mechanisms are not fully understood; it is not clear if changes to inhibitory control are specific to the presence of appetitive food cues. The dorsal anterior cingulate cortex (dACC) is central to inhibitory control and can be conceptualized selectively withholding ‘prepotent’ motor responses. This is driven by highly integrated glutamatergic and GABAergic neurotransmission. Temporal changes in glutamate, reflecting shifts in glutamate neurotransmission, can be detected under distinct processes or task conditions using [1]H fMRS. We investigated differences in dACC glutamate under task conditions with or without inhibitory motor control, utilizing neutral Squares and Food/Non-food stimuli, and their association with weight loss. Data were acquired from 13 individuals with obesity following dietary intervention resulting in 10% weight loss (5F; mean age: 50.1±5.2yrs). A visually-guided motor tapping task was used requiring participants to respond to stimuli under two modes, “Non-Selective” (motor responses to 100% of trials) and “Selective” (withholding responses on 20% of trials - involving both motor control and inhibition), and under two stimuli types (Squares and appetitive Food/Non-Food cues). Glutamate modulation changes (relative to the total signal) were assessed across stimuli type (independent of task mode) using repeated measures generalizing estimating equations (GEE) approach (SAS GENMOD). The correlation between glutamate during the Selective mode with food/non-food stimuli and percentage of weight lost during the dietary intervention was also assessed. The stimuli model term was not significant (χ2=3.50, p=0.174), but post hoc analysis indicated significantly increased glutamate during the Squares (z=-1.99, p=0.046), but not the Food/Non-food (z=-1.39, p=0.163) relative to baseline. A trending correlation between decreasing dACC glutamate modulation (Selective mode, Food/Non-Food) and decreasing percentage of weight lost during the intervention was observed (R2=0.274, F(1,11)=4.15, p=0.07). This suggests that the presence of appetitive food cues leads to a non-significant change in the dACC glutamate modulation independent of inhibitory or motor alone responses. The potential correlation between dACC glutamate modulation and weight loss provides preliminary support that appetitive food cues influence inhibitory control and the extent of the influences may be related to one’s ability to maintain weight loss. These results could provide greater understanding of the neurobiological mechanisms underlying top-down inhibitory processes influenced by affect and difficulties with weight loss and maintenance, potentially fueling better treatment for successful long-term WLM in obesity. Presentation: 6/1/2024

Involvement of the serotonergic, GABAergic and glutamatergic systems of the rostral anterior cingulate cortex in the trait and state anxiety of adult male Wistar rats.

Despite significant advancements to understand of the neural circuitry involved in anxiety, the neurobiology of trait anxiety remains unclear. The rostral anterior cingulate cortex (rACC) and various pathways have been implicated in its regulation, making it a key to trait anxiety. The present study aimed to investigate the role of these neurotransmitter systems in the rACC in trait anxiety. Since trait anxiety is known to modulate state anxiety, we further investigated this relationship. Specifically, in Experiment I, we used animals with high trait anxiety; in Experiment II, we used animals with low trait anxiety; and in Experiment III, we used animals with medium trait anxiety. Before each behavioral assessment, drugs that either increased or decreased serotonergic (Fluoxetine or WAY-100635), GABAergic (Muscimol or Bicuculline), and glutamatergic (NMDA or Ketamine) neurotransmission in the rACC were administered, along with their respective controls. Additionally, in Experiment IV, all animals from the previous experiments were subjected to the Elevated Plus Maze (EPM) and Hole board (HB) test and evaluated without taking into account their trait anxiety levels. The results of the present study showed that, in Exp I, the modulation of the serotonergic, GABAergic and glutamatergic systems in the rACC decreased trait anxiety in highly anxious rats, while by submitting the animals to HB, the administration of fluoxetine increased state anxiety. In Exp II, the modulation of all systems increased trait anxiety in rats with low trait anxiety, whereas, in HB, state anxiety levels were increased with the administration of NMDA. In Exp III, only the modulation of the glutamatergic system, with NMDA, increased both trait and state anxiety levels. However, none of the evaluated neurotransmitter systems altered the state anxiety modeled in the EPM. Overall, the results of the present study provide new insights into the role of the neurotransmitter systems in the rACC in the regulation of trait anxiety and state anxiety.

TDCS and local scalp cooling do not change corticomotor and intracortical excitability in healthy humans

ObjectiveScalp cooling might increase the long-term potentiation (LTP)-like effect of transcranial direct current stimulation (tDCS) by reducing the threshold for after-effects according to metaplasticity and increasing electrical current density reaching the cortical neurons. We aimed to investigate whether priming scalp cooling potentiates the tDCS after-effect on motor cortex excitability. MethodsThis study had a randomized, parallel-arms, sham-controlled, double-blinded design with an adequately powered sample of 105 healthy subjects. Corticomotor and intracortical excitability were assessed with motor evoked potentials (MEP) from transcranial magnetic stimulation (TMS) in short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) paradigms. Subjects were randomly allocated into six intervention groups, including anodal and cathodal tDCS (1-mA/20-min), scalp cooling, and sham. MEPs were recorded before, immediately, and 15 min after the interventions. ResultsWe did not observe changes in MEP amplitude from single-pulse TMS, SICI, and ICF with any intervention protocol. ConclusionAnodal and cathodal tDCS did not have an LTP-like neuromodulatory effect on corticospinal and did not provide detectable GABAergic and glutamatergic neurotransmission changes, which were not influenced by priming scalp cooling. SignificanceWe provide strong evidence that tDCS (1-mA/20-min) does not alter corticomotor and intracortical excitability with or without priming scalp cooling.

Metabotropic Glutamate Receptor 5 as a Potential Biomarker of the Intersection of Trauma and Cannabis Use.

Metabotropic glutamate receptor 5 (mGlu5) dysregulation has been implicated in the pathophysiology of trauma-related psychopathology, and there are direct interactions between the endocannabinoid and glutamatergic systems. However, relationships between cannabis use (CU) and mGlu5 have not been directly investigated in trauma-related psychopathology. Using positron emission tomography with [18F]FPEB, we examined relationships between CU status and mGlu5 availability in vivo in a cross-diagnostic sample of individuals with trauma-related psychopathology (n = 55). Specifically, we tested whether mGlu5 availability in frontolimbic regions of interest (ROIs; dorsolateral prefrontal cortex, orbitofrontal cortex, ventromedial prefrontal cortex, amygdala, hippocampus) differed as a function of CU status. Past-year CU (n = 22) was associated with 18.62%-19.12% higher mGlu5 availability in frontal and 14.24%-16.55% higher mGlu5 in limbic ROIs relative to participants with no recent CU. Similarly, past-month or monthly CU (n = 16) was associated with higher mGlu5 availability in frontal (18.05%-20.62%) and limbic (15.53%-16.83%) ROIs. mGlu5 availability in the orbitofrontal cortex and amygdala was negatively associated with depressive symptoms in the past-year CU group. In both CU groups, exploratory analyses showed negative correlations between mGlu5 availability and sadness across all ROIs and with perceptions of worthlessness and past failures (r's = -.47 to .66, P's = .006-.033) in the ventromedial prefrontal cortex. Participants with CU reported lower mean depressive symptoms (P's = .006-.037) relative to those without CU. These findings have substantial implications for our understanding of interactions between CU and glutamatergic neurotransmission in trauma-related psychopathology, underscoring the need for treatment development efforts to consider the effects of CU in this population.

Vasopressin regulates social play behavior in sex-specific ways through glutamate modulation in the lateral septum.

Understanding the neural basis of social play in juvenile rats may ultimately help restore social play deficits in autistic children. We previously found that administration of a vasopressin (AVP) V1a receptor (V1aR) antagonist into the lateral septum (LS) increased social play behavior in male juvenile rats and decreased it in females. Here, we demonstrate that glutamate, but not GABA, is involved in this sex-specific regulation. First, we found a sex difference in extracellular LS glutamate/GABA ratio (lower in females) that was eliminated by V1aR antagonist infusion in the LS that caused an increase in glutamate release in females only. Second, infusion of the glutamate receptor agonist L-glutamic acid into the LS mimicked the V1aR antagonist-induced decrease in female social play while preventing the increase in male social play. Third, infusion of the glutamate receptor antagonists AP-5 and CNQX into the LS prevented the V1aR antagonist-induced decrease in female social play. Fourth, there were no sex differences in extracellular GABA release in the LS upon either V1aR antagonist infusion or in social play expression upon infusion of the GABA-A receptor agonist muscimol into the LS, suggesting that GABA is not involved in the sex-specific regulation of social play by the LS-AVP system. Last, we found no sex differences in the type (GAD1/2, somatostatin, calbindin 1, Sox9) of V1aR-expressing LS cells, suggesting other cellular mechanisms mediating the sex-specific effects on glutamate release in the LS by the LS-AVP system. In conclusion, we demonstrate that the LS-AVP system regulates social play sex-specifically via glutamatergic neurotransmission. These findings have relevance for potential sex-specific effects of AVP-based treatment of social deficits in children.

Regional patterns of human cortex development correlate with underlying neurobiology

Human brain morphology undergoes complex changes over the lifespan. Despite recent progress in tracking brain development via normative models, current knowledge of underlying biological mechanisms is highly limited. We demonstrate that human cortical thickness development and aging trajectories unfold along patterns of molecular and cellular brain organization, traceable from population-level to individual developmental trajectories. During childhood and adolescence, cortex-wide spatial distributions of dopaminergic receptors, inhibitory neurons, glial cell populations, and brain-metabolic features explain up to 50% of the variance associated with a lifespan model of regional cortical thickness trajectories. In contrast, modeled cortical thickness change patterns during adulthood are best explained by cholinergic and glutamatergic neurotransmitter receptor and transporter distributions. These relationships are supported by developmental gene expression trajectories and translate to individual longitudinal data from over 8000 adolescents, explaining up to 59% of developmental change at cohort- and 18% at single-subject level. Integrating neurobiological brain atlases with normative modeling and population neuroimaging provides a biologically meaningful path to understand brain development and aging in living humans.

Mitigation of synaptic and memory impairments via F-actin stabilization in Alzheimer’s disease

BackgroundSynaptic dysfunction, characterized by synapse loss and structural alterations, emerges as a prominent correlate of cognitive decline in Alzheimer’s disease (AD). Actin cytoskeleton, which serves as the structural backbone of synaptic architecture, is observed to be lost from synapses in AD. Actin cytoskeleton loss compromises synaptic integrity, affecting glutamatergic receptor levels, neurotransmission, and synaptic strength. Understanding these molecular changes is crucial for developing interventions targeting synaptic dysfunction, potentially mitigating cognitive decline in AD.MethodsIn this study, we investigated the synaptic actin interactome using mass spectrometry in a mouse model of AD, APP/PS1. Our objective was to explore how alterations in synaptic actin dynamics, particularly the interaction between PSD-95 and actin, contribute to synaptic and cognitive impairment in AD. To assess the impact of restoring F-actin levels on synaptic and cognitive functions in APP/PS1 mice, we administered F-actin stabilizing agent, jasplakinolide. Behavioral deficits in the mice were evaluated using the contextual fear conditioning paradigm. We utilized primary neuronal cultures to study the synaptic levels of AMPA and NMDA receptors and the dynamics of PSD-95 actin association. Furthermore, we analyzed postmortem brain tissue samples from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer’s dementia (AD) to determine the association between PSD-95 and actin.ResultsWe found a significant reduction in PSD-95-actin association in synaptosomes from middle-aged APP/PS1 mice compared to wild-type (WT) mice. Treatment with jasplakinolide, an actin stabilizer, reversed deficits in memory recall, restored PSD-95-actin association, and increased synaptic F-actin levels in APP/PS1 mice. Additionally, actin stabilization led to elevated synaptic levels of AMPA and NMDA receptors, enhanced dendritic spine density, suggesting improved neurotransmission and synaptic strength in primary cortical neurons from APP/PS1 mice. Furthermore, analysis of postmortem human tissue with NCI, MCI and AD subjects revealed disrupted PSD-95-actin interactions, underscoring the clinical relevance of our preclinical studies.ConclusionOur study elucidates disrupted PSD-95 actin interactions across different models, highlighting potential therapeutic targets for AD. Stabilizing F-actin restores synaptic integrity and ameliorates cognitive deficits in APP/PS1 mice, suggesting that targeting synaptic actin regulation could be a promising therapeutic strategy to mitigate cognitive decline in AD.

Cell type-specific and subcellular expression of phospholipid phosphatase-related proteins to modulate lyso-phosphatidic acid synaptic signaling in the developing and adult CNS.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that participates in critical processes in neural development and adult brain function and is implicated in various pathophysiological conditions. Along with its six well-characterized receptors, atypical regulators of LPA signaling have also been suggested, including phospholipid phosphatase-related proteins (PLPPRs). PLPPRs have been mostly studied in the developing brain where they control LPA-dependent axon guidance, cortical network hyperexcitability, and glutamatergic neurotransmission. PLPPR4 and PLPPR3 represent two closely related proteins reported to localize predominantly in dendrites and axons, respectively, and differ in their developmental expression patterns. Herein, we have revised the expression patterns of PLPPRs in the cerebellum, dorsal and ventral hippocampus, prefrontal cortex (PFC), nucleus accumbens, and striatum during development and in the adult using quantitative PCR. Expression patterns of Plppr2,4 and 5 were consistent with previous studies, whereas Plppr3 and Plppr1 exhibited a unique expression profile in nucleus accumbens (NAc) and striatum in later developmental and adult stages, which we verified at the protein level for PLPPR3. To investigate neuron type-specific expression at the single cell level, we developed a bioinformatic tool to analyze recent single-cell RNA-sequencing data in the cerebral cortex and hippocampus of adult mice. Our analysis revealed a widespread but also selective adult neuron-type expression with higher expression levels of Plppr3, Plppr1, and Plppr5 in GABAergic and Plppr4 and Plppr2 in glutamatergic neurons. PLPPR4 has been identified as a post-synaptic modulator of LPA levels in glutamatergic synapses operating via an uptake mechanism, to control LPA-dependent cortical network hyperexcitability. Using subcellular fractionation experiments, we found that both PLPPR4 and PLPPR3 are co-expressed in adult synaptosomal membranes. Furthermore, flow cytometry experiments in HEK293 cells showed comparable LPA uptake by PLPPR4 and PLPPR3, whereas PLPRR3, but not PLPPR4, induced also uptake of monoacylglycerol, the dephosphorylation product of LPA. We propose that synaptic LPA may be subject to both pre-synaptic and post-synaptic mechanisms of regulation by PLPPRs in addition to LPARs in developing and adult synapses.

Auvelity: A New Era in Medicine - Unraveling the Multifaceted Benefits of Dextromethorphan/Bupropion Combination

Background: Depression is a prevalent global illness, impacting 280 million people worldwide, and Major Depressive Disorder (MDD) is ranked as the third leading cause of disease burden globally. People previously diagnosed with depression are more likely to develop Alzheimer's disease (AD). The recent approval of Auvelity by the FDA has made a remarkable breakthrough in drug development, offering a multi-dimensional approach for managing multiple diseases. Objective: The main objective of this study is to investigate the role of Auvelity, a new drug, in treating MDD and its potential to manage agitation in individuals with Alzheimer's disease (AD). Methodology: Data on Auvelity was collected from various sources, including accessdata.fda.gov, PubMed, and Scopus, and compiled for analysis Discussion: Auvelity is the first oral medication to demonstrate the rapid onset of action, with statistically significant antidepressant efficacy observed as early as one week compared to a placebo. It contains a combination of dextromethorphan (45 mg) and bupropion (105 mg). The drug's mechanism of action involves a combination of NMDA receptor blockade and agonism of the sigma-1 receptor, resulting in the antagonization of the glutamatergic neurotransmitter pathway. Due to the similarity in the mechanism of action with AD medications like Memantine, there is a hypothesis that Auvelity could effectively reduce symptoms of AD. Conclusion: The approval of Auvelity marks a significant advancement in depression treatment with its unique NMDA antagonist mechanism, rapid onset of action, and low-risk profile.

Cell-specific expression of key mitochondrial enzymes limits OXPHOS in astrocytes of the adult human neocortex and hippocampal formation

The astrocyte-to-neuron lactate shuttle model entails that, upon glutamatergic neurotransmission, glycolytically derived pyruvate in astrocytes is mainly converted to lactate instead of being entirely catabolized in mitochondria. The mechanism of this metabolic rewiring and its occurrence in human brain are unclear. Here by using immunohistochemistry (4 brains) and imaging mass cytometry (8 brains) we show that astrocytes of the adult human neocortex and hippocampal formation express barely detectable amounts of mitochondrial proteins critical for performing oxidative phosphorylation (OXPHOS). These data are corroborated by queries of transcriptomes (107 brains) of neuronal versus non-neuronal cells fetched from the Allen Institute for Brain Science for genes coding for a much larger repertoire of entities contributing to OXPHOS, showing that human non-neuronal elements barely expressed mRNAs coding for such proteins. With less OXPHOS, human brain astrocytes are thus bound to produce more lactate to avoid interruption of glycolysis.

Role of peripheral inflammation in minimal hepatic encephalopathy.

Many patients with liver cirrhosis show minimal hepatic encephalopathy (MHE) with mild cognitive impairment (MCI) and motor alterations that reduce their quality of life. Some patients with steatotic liver disease also suffer MCI. To design treatments to improve MHE/MCI it is necessary to understand the mechanisms by which liver disease induce them. This review summarizes studies showing that appearance of MHE/MCI is associated with a shift in the immunophenotype leading to an "autoimmune-like" form with increased pro-inflammatory monocytes, enhanced CD4 T and B lymphocytes activation and increased plasma levels of pro-inflammatory cytokines, including IL-17, IL-21, TNFα, IL-15 and CCL20. The contribution of peripheral inflammation to trigger MHE is supported by studies in animal models and by the fact that rifaximin treatment reverses MHE in around 60% of patients in parallel with reversal of the changes in peripheral inflammation. MHE does not improve in patients in which peripheral inflammation is not improved by rifaximin. The process by which peripheral inflammation induces MHE involves induction of neuroinflammation in brain, with activation of microglia and astrocytes and increased pro-inflammatory TNFα and IL-1β, which is observed in patients who died with steatotic liver disease (SLD) or liver cirrhosis and in animal models of MHE. Neuroinflammation alters glutamatergic and GABAergic neurotransmission, leading to cognitive and motor impairment. Transmission of peripheral alterations into the brain is mediated by infiltration in brain of extracellular vesicles from plasma and of cells from the peripheral immune system. Acting on any step of the process peripheral inflammation - neuroinflammation - altered neurotransmission may improve MHE.

Correlation between compulsive behaviors and plastic changes in the dendritic spines of the prefrontal cortex and dorsolateral striatum of male rats

Obsessive-compulsive disorder (OCD) is a mental affliction characterized by compulsive behaviors often manifested in intrusive thoughts and repetitive actions. The quinpirole model has been used with rats to replicate compulsive behaviors and study the neurophysiological processes associated with this pathology. Several changes in the dendritic spines of the medial prefrontal cortex (mPFC) and dorsolateral striatum (DLS) have been related to the occurrence of compulsive behaviors. Dendritic spines regulate excitatory synaptic contacts, and their morphology is associated with various brain pathologies. The present study was designed to correlate the occurrence of compulsive behaviors (generated by administering the drug quinpirole) with the morphology of the different types of dendritic spines in the mPFC and DLS. A total of 18 male rats were used. Half were assigned to the experimental group, the other half to the control group. The former received injections of quinpirole, while the latter rats were injected with physiological saline solution, for 10 days in both cases. After the experimental treatment, the quinpirole rats exhibited all the parameters indicative of compulsive behavior and a significant correlation with the density of stubby and wide neckless spines in both the mPFC and DLS. Dendritic spines from both mPFC and DLS neurons showed plastic changes correlatively with the expression of compulsive behavior induced by quinpirole. Further studies are suggested to evaluate the involvement of glutamatergic neurotransmission in the neurobiology of OCD.