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The neurotensin system spans across the central nervous system, to the enteric nervous system (gut), and the periphery to govern behaviors and physiological responses that tune energy balance to maintain homeostasis. Neurotensin transmission is not only modulated by metabolic signals, neurotensin transmission itself can also impact metabolic state by exerting control over consumption, physical activity, and satiety signals. Many responses to sensory experiences and sleep processes are dictated by neurotensinergic activity via mechanisms that allow the organism to balance energy seeking and utilization to thrive in its environment. Given the broad reach neurotensin signaling has across the homeostatic landscape, understanding this system as a whole and examining new ways to target this system for therapeutic efficacy across many different conditions is necessary. [ABSTRACT FROM AUTHOR]

In several neurodegenerative diseases, however, ectopic neuronal cell cycle events are found associated with regions of neuronal death. In the paper by Zhu et al., the authors use abnormal neuronal cell cycle activity as a screen to test natural compounds derived from marine bacteria for their potential in preventing it and thus acting as neuroprotective agents. B Image content: b This image shows cerebellar Purkinje cells in one-month old mouse model of ataxia-telangiectasia, a neurodegenerative disease. [Extracted from the article]

l-glutamate (Glu) is the main excitatory neurotransmitter in the central nervous system (CNS) and is associated with motor behavior and sensory perception. While microdialysis methods have been used to record tonic levels of Glu, little is known about the more rapid changes in Glu signals that may be observed in awake rats. We have reported acute recording methods using enzyme-based microelectrode arrays (MEA) with fast response time and low detection levels of Glu in anesthetized animals with minimal interference. The current paper concerns modification of the MEA design to allow for reliable measures in the brain of conscious rats. In this study, we characterized the effects of chronic implantation of the MEA into the brains of rats. We were capable of measuring Glu levels for 7 days without loss of sensitivity. We performed studies of tail-pinch induced stress, which caused a robust biphasic increase in Glu. Histological data show chronic implantation of the MEAs caused minimal injury to the CNS. Taken together, our data show that chronic recordings of tonic and phasic Glu can be carried out in awake rats for up to 17 days in vivo allowing longer term studies of Glu regulation in behaving rats.

l-glutamate (Glu) is the main excitatory neurotransmitter in the central nervous system (CNS) and is associated with motor behavior and sensory perception. While microdialysis methods have been used to record tonic levels of Glu, little is known about the more rapid changes in Glu signals that may be observed in awake rats. We have reported acute recording methods using enzyme-based microelectrode arrays (MEA) with fast response time and low detection levels of Glu in anesthetized animals with minimal interference. The current paper concerns modification of the MEA design to allow for reliable measures in the brain of conscious rats. In this study, we characterized the effects of chronic implantation of the MEA into the brains of rats. We were capable of measuring Glu levels for 7 days without loss of sensitivity. We performed studies of tail-pinch induced stress, which caused a robust biphasic increase in Glu. Histological data show chronic implantation of the MEAs caused minimal injury to the CNS. Taken together, our data show that chronic recordings of tonic and phasic Glu can be carried out in awake rats for up to 17 days in vivo allowing longer term studies of Glu regulation in behaving rats. [ABSTRACT FROM AUTHOR]

In Aplysia, the neurotransmitter dopamine is involved in the regulation of various physiological processes and motor functions, like feeding behaviour, and in the siphon-gill withdrawal reflex. In this paper, we report the characterization of the first Aplysia D1-like dopamine receptor (Apdop1) mainly expressed in the CNS, heart and buccal mass. Following expression of the Apdop1 receptor in HEK293 cells, a higher level of cAMP was observed in the absence of the receptor ligand, showing that Apdop1 is constitutively active. This activity was blocked by the inverse agonist flupentixol. Application of dopamine (EC50 of 35 nm) or serotonin (EC50 of 36 μm) to Apdop1-transfected HEK293 cells further increased the level of cAMP, suggesting that the receptor is linked to the stimulatory Gs protein pathway. When expressed in cultured sensory neurons, Apdop1 immunoreactivity was observed in the cell body and neurites. Control sensory neurons responded to dopamine with a decrease in excitability mediated by a pertusis toxin-sensitive G protein. Expression of Apdop1 produced an increase in hyperpolarization in the absence of agonist and an increase in membrane excitability following stimulation by dopamine. In the presence of pertussis toxin to inhibit the Gi protein inhibitory pathway responsible for decrease in excitability mechanism, Stimulation of membrane excitability was observed. Apdop1 sensitivity to dopamine makes it a potential modulator of operant conditioning procedure. [ABSTRACT FROM AUTHOR]

Microglia have been implicated in multiple sclerosis (MS) pathogenesis. The fractalkine receptor CX3CR1 limits the activation of pathogenic microglia and the human polymorphic CX3CR1I249/M280 (hCX3CR1I249/M280) variant increases disease progression in models of MS. However, the role of hCX3CR1I249/M280 variant on microglial activation and central nervous system repair mechanisms remains unknown. Therefore, using transgenic mice expressing the hCX3CR1I249/M280 variant, we aimed to determine the contribution of defective CX3CR1 signaling to neuroinflammation and remyelination in the cuprizone model of focal demyelination. Here, we report that mice expressing hCX3CR1I249/M280 exhibit marked demyelination and microgliosis following acute cuprizone treatment. Nanostring gene expression analysis in demyelinated lesions showed that hCX3CR1I249/M280 but not CX3CR1‐deficient mice up‐regulated the cuprizone‐induced gene profile linked to inflammatory, oxidative stress, and phagocytic pathways. Although CX3CR1‐deficient (CX3CR1‐KO) and fractalkine‐deficient (FKN‐KO) mice displayed a comparable demyelination and microglial activation phenotype to hCX3CR1I249/M280 mice, only CX3CR1‐deficient and CX3CR1‐WT mice showed significant myelin recovery 1 week from cuprizone withdrawal. Confocal microscopy showed that hCX3CR1I249/M280 variant inhibits the generation of cells involved in myelin repair. Our results show that defective fractalkine signaling contributes to regional differences in demyelination, and suggest that the CX3CR1 pathway activity may be a key mechanism for limiting toxic gene responses in neuroinflammation. Cover Image for this issue: https://doi.org/10.1111/jnc.15416 [ABSTRACT FROM AUTHOR]

Oligodendrocytes are the glial cells responsible for the formation of myelin around axons of the central nervous system (CNS). Myelin is an insulating layer that allows electrical impulses to transmit quickly and efficiently along neurons. If myelin is damaged, as in chronic demyelinating disorders such as multiple sclerosis (MS), these impulses slow down. Remyelination by oligodendrocytes is often ineffective in MS, in part because of the failure of oligodendrocyte precursor cells (OPCs) to differentiate into mature, myelinating oligodendrocytes. The process of oligodendrocyte differentiation is tightly controlled by several regulatory networks involving transcription factors, intracellular signaling pathways, and extrinsic cues. Understanding the factors that regulate oligodendrocyte development is essential for the discovery of new therapeutic strategies capable of enhancing remyelination. Over the past decade, microRNAs (miRNAs) have emerged as key regulators of oligodendrocyte development, exerting effects on cell specification, proliferation, differentiation, and myelination. This article will review the role of miRNAs on oligodendrocyte biology and discuss their potential as promising therapeutic tools for remyelination. [ABSTRACT FROM AUTHOR]

Mechanisms that determine the survival of midbrain dopaminergic (mDA) neurons in the adult central nervous system (CNS) are not fully understood. Netrins are a family of secreted proteins that are essential for normal neural development. In the mature CNS, mDA neurons express particularly high levels of netrin‐1 and its receptor Deleted in Colorectal Cancer (DCC). Recent findings indicate that overexpressing netrin‐1 protects mDA neurons in animal models of Parkinson's disease (PD), with a proposed pro‐apoptotic dependence function for DCC that triggers cell death in the absence of a ligand. Here, we sought to determine if DCC expression influences mDA neuron survival in young adult and ageing mice. To circumvent the perinatal lethality of DCC null mice, we selectively deleted DCC from mDA neurons utilizing DATcre/loxP gene‐targeting and examined neuronal survival in adult and aged animals. Reduced numbers of mDA neurons were detected in the substantia nigra pars compacta (SNc) of young adult DATcre/DCCfl/fl mice, with further reduction in aged DATcre/DCCfl/fl animals. In contrast to young adults, aged mice also exhibited a gene dosage effect, with fewer SNc mDA neurons in DCC heterozygotes (DATcre/DCCfl/wt). Notably, loss of mDA neurons in the SN was not uniform. Neuronal loss in the SN was limited to ventral tier mDA neurons, while mDA neurons in the dorsal tier of the SN, which resist degeneration in PD, were spared from the effect of DCC deletion in both young and aged mice. In the ventral tegmental area (VTA), young adult mice with conditional deletion of DCC had normal mDA neuronal numbers, while significant loss occurred in aged DATcre/DCCfl/fl and DATcre/DCCfl/wt mice compared to age‐matched wild‐type mice. Our results indicate that expression of DCC is required for the survival of subpopulations of mDA neurons and may be relevant to the degenerative processes in PD. [ABSTRACT FROM AUTHOR]

In aged mice (16 months), total midbrain TH cell numbers were lower in both DCC knockout and heterozygote mice than in wildtypes, and TH cell numbers in both the substantia nigra and ventral tegmental area were lower in DCC knockout and heterozygote mice than in wildtypes. B Front cover b Increasing evidence suggests the involvement of peripheral amino acid metabolism in the pathophysiology of neuropsychiatric disorders, whereas the molecular mechanisms are largely unknown. Inhibiting 1-adrenergic receptor signaling pathway ameliorates AD-type pathologies and behav... Z-Y. Yu, X. Yi, Y-R. Wang, G-H. Zeng, C-R. Tan, Y. Cheng, P-Y. Sun, Z-H. Liu, Y-J. Wang and Y-H. Liu Inhibition of the 1 adrenergic receptors ( 1-ARs) signaling pathway ameliorates behavioral deficits and Alzheimer's disease (AD)-type pathologies, including deposition of amyloid-beta (A ), tau hyperphosphorylation, neuroinflammation, and neurodegeneration. [Extracted from the article]

Cholinergic transmission underlies higher brain functions such as cognition and movement. To elucidate the process whereby acetylcholine (ACh) release is maintained and regulated in the central nervous system, uptake of [3H]choline and subsequent synthesis and release of [3H]ACh were investigated in rat striatal segments. Incubation with [3H]choline elicited efficient uptake via high‐affinity choline transporter‐1, resulting in accumulation of [3H]choline and [3H]ACh. However, following inhibition of ACh esterase (AChE), incubation with [3H]choline led predominantly to the accumulation of [3H]ACh. Electrical stimulation and KCl depolarization selectively released [3H]ACh but not [3H]choline. [3H]ACh release gradually declined upon repetitive stimulation, whereas the release was reproducible under inhibition of AChE. [3H]ACh release was abolished after treatment with vesamicol, an inhibitor of vesicular ACh transporter. These results suggest that releasable ACh is continually replenished from the cytosol to releasable pools of cholinergic vesicles to maintain cholinergic transmission. [3H]ACh release evoked by electrical stimulation was abolished by tetrodotoxin, but that induced by KCl was largely resistant. ACh release was Ca2+ dependent and exhibited slightly different sensitivities to N‐ and P‐type Ca2+ channel toxins (ω‐conotoxin GVIA and ω‐agatoxin IVA, respectively) between both stimuli. [3H]ACh release was negatively regulated by M2 muscarinic and D2 dopaminergic receptors. The present results suggest that inhibition of AChE within cholinergic neurons and of presynaptic negative regulation of ACh release contributes to maintenance and facilitation of cholinergic transmission, providing a potentially useful clue for the development of therapies for cholinergic dysfunction‐associated disorders, in addition to inhibition of synaptic cleft AChE. [ABSTRACT FROM AUTHOR]

Adaptation to acute and chronic stress and/or persistent stressors is a subject of wide interest in central nervous system disorders. In this context, stress is an effector of change in organismal homeostasis and the response is generated when the brain perceives a potential threat. Herein, we discuss a nuanced and granular view whereby a wide variety of genotoxic and environmental stressors, including aging, genetic risk factors, environmental exposures, and age‐ and lifestyle‐related changes, act as direct insults to cellular, as opposed to organismal, homeostasis. These two concepts of how stressors impact the central nervous system are not mutually exclusive. We discuss how maladaptive stressor‐induced changes in protein connectivity through epichaperomes, disease‐associated pathologic scaffolds composed of tightly bound chaperones, co‐chaperones, and other factors, impact intracellular protein functionality altering phenotypes, that in turn disrupt and remodel brain networks ranging from intercellular to brain connectome levels. We provide an evidence‐based view on how these maladaptive changes ranging from stressor to phenotype provide unique precision medicine opportunities for diagnostic and therapeutic development, especially in the context of neurodegenerative disorders including Alzheimer's disease where treatment options are currently limited. [ABSTRACT FROM AUTHOR]

Erythropoietin (Epo), the main erythropoiesis‐stimulating factor widely prescribed to overcome anemia, is also known nowadays for its cytoprotective action on non‐hematopoietic tissues. In this context, Epo showed not only its ability to cross the blood‐brain barrier, but also its expression in the brain of mammals. In clinical trials, recombinant Epo treatment has been shown to stimulate neurogenesis; improve cognition; and activate antiapoptotic, antioxidant, and anti‐inflammatory signaling pathways. These mechanisms, proposed to characterize a neuroprotective property, opened new perspectives on the Epo pharmacological potencies. However, many questions arise about a possible physiological role of Epo in the central nervous system (CNS) and the factors or environmental conditions that induce its expression. Although Epo may be considered a strong candidate to be used against neuronal damage, long‐term treatments, particularly when high Epo doses are needed, may induce thromboembolic complications associated with increases in hematocrit and blood viscosity. To avoid these adverse effects, different Epo analogs without erythropoietic activity but maintaining neuroprotection ability are currently being investigated. Carbamylated erythropoietin, as well as alternative molecules like Epo fusion proteins and partial peptides of Epo, seems to match this profile. This review will focus on the discussion of experimental evidence reported in recent years linking erythropoietin and CNS function through investigations aimed at finding benefits in the treatment of neurodegenerative diseases. In addition, it will review the proposed mechanisms for novel derivatives which may clarify and, eventually, improve the neuroprotective action of Epo. [ABSTRACT FROM AUTHOR]

Intracellular signaling pathways that promote axon regeneration are closely linked to the mechanism of neurite outgrowth. TC10, a signaling molecule that acts on neurite outgrowth through membrane transport, is a member of the Rho family G proteins. Axon injury increases the TC10 levels in motor neurons, suggesting that TC10 may be involved in axon regeneration. In this study, we tried to understand the roles of TC10 in the nervous system using TC10 knock‐out mice. In cultured hippocampal neurons, TC10 ablation significantly reduced axon elongation without affecting ordinary polarization. We determined a role of TC10 in microtubule stabilization at the growth cone neck; therefore, we assume that TC10 limits axon retraction and promotes in vitro axon outgrowth. In addition, there were no notable differences in the size and structure of brains during prenatal and postnatal development between wild‐type and TC10 knock‐out mice. In motor neurons, axon regeneration after injury was strongly suppressed in mice lacking TC10 (both in conventional and injured nerve specific deletion). In retinal ganglion cells, TC10 ablation suppressed the axon regeneration stimulated by intraocular inflammation and cAMP after optic nerve crush. These results show that TC10 plays an important role in axon regeneration in both the peripheral and central nervous systems, and the role of TC10 in peripheral axon regeneration is neuron‐intrinsic. [ABSTRACT FROM AUTHOR]

Artemisinin and its derivatives have been the frontline drugs for treating malaria. In addition to the antiparasitic effect, accumulating evidence shows that artemisinins can alleviate neuroinflammatory responses in the central nervous system (CNS). However, the precise mechanisms underlying their anti‐neuroinflammatory effects are unclear. Herein we attempted to delineate the molecule target of artemisinin in microglia. In vitro protein intrinsic fluorescence titrations and saturation transfer difference (STD)‐NMR showed the direct binding of artemisinin to Toll‐like receptor TLR4 co‐receptor MD2. Cellular thermal shift assay (CETSA) showed that artemisinin binding increased MD2 stability, which implies that artemisinin directly binds to MD2 in the cellular context. Artemisinin bound MD2 showed much less collapse during the molecular dynamic simulations, which supports the increased stability of MD2 upon artemisinin binding. Flow cytometry analysis showed artemisinin inhibited LPS‐induced TLR4 dimerization and endocytosis in microglial BV‐2 cells. Therefore, artemisinin was found to inhibit the TLR4‐JNK signaling axis and block LPS‐induced pro‐inflammatory factors nitric oxide, IL‐1β and TNF‐α in BV‐2 cells. Furthermore, artemisinin restored LPS‐induced decrease of junction proteins ZO‐1, Occludin and Claudin‐5 in primary brain microvessel endothelial cells, and attenuated LPS‐induced blood–brain barrier disruption in mice as assessed by Evans blue. In all, this study unambiguously adds MD2 as a direct binding target of artemisinin in its anti‐neuroinflammatory function. The results also suggest that artemisinin could be repurposed as a potential therapeutic intervention for inflammatory CNS diseases. [ABSTRACT FROM AUTHOR]

HIV‐associated neurocognitive disorders (HAND) are common features of the effect of human immunodeficiency virus (HIV)‐1 within the central nervous system (CNS). The underlying neuropathophysiology of HAND is incompletely known. Furthermore, there are no markers to effectively predict or stratify the risk of HAND. Recent advancements in the fields of proteomics and metabolomics have shown promise in addressing these concerns, however, it is not clear if these approaches may provide new insight into pathways and markers related to HAND. We therefore conducted a systematic review of studies using proteomic and/or metabolomic approaches in the aim of identifying pathways or markers associated with neurocognitive impairment in people living with HIV (PLWH). Thirteen studies were eligible, including 11 proteomic and 2 metabolomic investigations of HIV‐positive clinical samples (cerebrospinal fluid (CSF), brain tissue, and serum). Across varying profiling techniques and sample types, the majority of studies found an association of markers with neurocognitive function in PLWH. These included metabolic marker myo‐inositol and proteomic markers superoxide dismutase, gelsolin, afamin, sphingomyelin, and ceramide. Certain markers were found to be dysregulated across various sample types. Afamin and gelsolin overlapped in studies of blood and CSF and sphingomyelin and ceramide overlapped in studies of CSF and brain tissue. The association of these markers with neurocognitive functioning may indicate the activity of certain pathways, potentially those related to the underlying neuropathophysiology of HAND. [ABSTRACT FROM AUTHOR]

The article presents an abstract of the research paper "Diet, lipids and brain development." Formation of a myelin sheath is one of the fundamental and necessary events in the normal development of the central nervous system in vertebrates. Myelinogenesis is basically a postnatal process in rodents.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease which involves functional and structural defects in selective central nervous system (CNS) regions that harm function and individual ability to process and respond to external stimuli. Individuals with ASD spend less time engaging in social interaction compared to non‐affected subjects. Studies employing structural and functional magnetic resonance imaging reported morphological and functional abnormalities in the connectivity of the mesocorticolimbic reward pathway between the nucleus accumbens and the ventral tegmental area (VTA) in response to social stimuli, as well as diminished medial prefrontal cortex in response to visual cues, whereas stronger reward system responses for the non‐social realm (e.g., video games) than social rewards (e.g., approval), associated with caudate nucleus responsiveness in ASD children. Defects in the mesocorticolimbic reward pathway have been modulated in transgenic murine models using D2 dopamine receptor heterozygous (D2+/−) or dopamine transporter knockout mice, which exhibit sociability deficits and repetitive behaviors observed in ASD phenotypes. Notably, the mesocorticolimbic reward pathway is modulated by systemic and central inflammation, such as primed microglia, which occurs during obesity or maternal overnutrition. Therefore, we propose that a positive energy balance during obesity/maternal overnutrition coordinates a systemic and central inflammatory crosstalk that modulates the dopaminergic neurotransmission in selective brain areas of the mesocorticolimbic reward pathway. Here, we will describe how obesity/maternal overnutrition may prime microglia, causing abnormalities in dopamine neurotransmission of the mesocorticolimbic reward pathway, postulating a possible immune role in the development of ASD. [ABSTRACT FROM AUTHOR]

Glioblastomas (GBMs) are highly aggressive primary brain tumors characterized by cellular heterogeneity, insensitivity to chemotherapy and poor patient survival. Lysophosphatidic acid (LPA) is a lysophospholipid that acts as a bioactive signaling molecule and plays important roles in diverse biological events during development and disease, including several cancer types. Microglial cells, the resident macrophages of the central nervous system, express high levels of Autotaxin (ATX,Enpp2), an enzyme that synthetizes LPA. Our study aimed to investigate the role of LPA on tumor growth and invasion in the context of microglia‐GBM interaction. First, through bioinformatics studies, patient data analysis demonstrated that more aggressive GBM expressed higher levels of ENPP2, which was also associated with worse patient prognosis with proneural GBM. Using GBM‐microglia co‐culture system we then demonstrated that GBM secreted factors were able to increase LPA1 and ATX in microglia, which could be further enhanced by hypoxia. On the other hand, interaction with microglial cells also increased ATX expression in GBM. Furthermore, microglial‐induced GBM proliferation and migration could be inhibited by pharmacological inhibition of LPA1, suggesting that microglial‐derived LPA could support tumor growth and invasion. Finally, increased LPA1 expression was observed in GBM comparing with other gliomas and could be also associated with worse patient survival. These results show for the first time a microglia‐GBM interaction through the LPA pathway with relevant implications for tumor progression. A better understanding of this interaction can lead to the development of new therapeutic strategies setting LPA as a potential target for GBM treatment. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is a movement disorder that is characterized by an uncomfortable sensation in the legs, and the urge to move the legs. Meis1 has previously identified as a risk gene for RLS. This Editorial highlights the study by Lyu and colleagues who developed a novel genetic mouse model heterozygous for Meis1 expression in neurons of the central nervous system. Using behavioral tests, the authors established hyperactivity of the mice, reminiscent of symptoms found in RLS patients. In addition, the authors took a closer look at the iron, dopaminergic, and cholinergic system of these mice. [ABSTRACT FROM AUTHOR]

Damaged axons in the adult mammalian central nervous system have a restricted regenerative capacity mainly because of Nogo protein, which is a major myelin‐associated axonal growth inhibitor with binding to both receptors of Nogo receptor‐1 (NgR1) and paired immunoglobulin‐like receptor (PIR)‐B. Lateral olfactory tract usher substance (LOTUS) exerts complete suppression of NgR1‐mediated axonal growth inhibition by antagonizing NgR1. However, the regulation of PIR‐B functions in neurons remains unknown. In this study, protein–protein interactions analyses found that LOTUS binds to PIR‐B and abolishes Nogo‐binding to PIR‐B completely. Reverse transcription‐polymerase chain reaction and immunocytochemistry revealed that PIR‐B is expressed in dorsal root ganglions (DRGs) from wild‐type and Ngr1‐deficient mice (male and female). In these DRG neurons, Nogo induced growth cone collapse and neurite outgrowth inhibition, but treatment with the soluble form of LOTUS completely suppressed them. Moreover, Nogo‐induced growth cone collapse and neurite outgrowth inhibition in Ngr1‐deficient DRG neurons were neutralized by PIR‐B function‐blocking antibodies, indicating that these Nogo‐induced phenomena were mediated by PIR‐B. Our data show that LOTUS negatively regulates a PIR‐B function. LOTUS thus exerts an antagonistic action on both receptors of NgR1 and PIR‐B. This may lead to an improvement in the defective regeneration of axons following injury. [ABSTRACT FROM AUTHOR]

Nicotinic acetylcholine receptors (nAChRs) are major signalling molecules in the central and peripheral nervous system. Over the last decade, they have been linked to a number of major human psychiatric and neurological conditions, like smoking, schizophrenia, Alzheimer's disease and many others. Human Genome‐Wide Association Studies (GWAS) have robustly identified genetic alterations at a locus of chromosome 15q to several of these diseases. In this review, we discuss a major coding polymorphism in the alpha5 subunit, referred to as α5SNP, and its functional dissection in vitro and in vivo. Its presence at high frequency in many human populations lends itself to pharmaceutical intervention in the context of 'positive allosteric modulators' (PAMs). We will present the prospects of this novel treatment, and the remaining challenges to identify suitable molecules. [ABSTRACT FROM AUTHOR]

Local anesthetics can cause severe toxicity when absorbed systemically. Rapid intravenous administration of lipid emulsion (LE) is the standard of care for severe local anesthetic systemic toxicity which can cause cardiovascular and central nervous system (CNS) injury. The biological mechanism by which LE alleviates CNS toxicity remains unknown and understudied. Previous research has suggested that local anesthetics cause an imbalance of excitatory and inhibitory transmission in the brain. Therefore, this study aimed to observe the effect of LE on glutamate‐ and GABA‐induced currents in CA1 pyramidal neurons after bupivacaine‐induced CNS toxicity. We further characterized post‐synaptic modifications in these cells to try to elucidate the mechanism by which LE mediates bupivacaine‐induced CNS toxicity. Sprague–Dawley rats received intravenous bupivacaine (1 mg kg−1 min−1) in either normal saline or LE (or LE without bupivacaine) for 5 min. An acute brain slice preparation and a combination of whole‐cell patch clamp techniques and whole‐cell recordings were used to characterize action potential properties, miniature excitatory, and inhibitory post‐synaptic currents, and post‐synaptic modifications of excitatory and inhibitory transmission in CA1 hippocampal pyramidal neurons. The expression level of GABAA receptors were assessed with western blotting, whereas H&E and TUNEL staining were used to assess cytoarchitecture and apoptosis levels respectively. Bupivacaine treatment significantly increased the number of observed action potentials, whereas significantly decreasing rheobase, the first interspike interval (ISI), and hyperpolarization‐activated cation currents (Ih) in CA1 pyramidal neurons. LE treatment significantly reduced the frequency of miniature inhibitory post‐synaptic currents and enhanced GABA‐induced paired pulse ratio with 50 ms interval stimulation in bupivacaine‐treated rats. Regulation of GABAA levels is a promising mechanism by which LE may ameliorate CNS toxicity after systemic absorption of bupivacaine. [ABSTRACT FROM AUTHOR]

Minimal hepatic encephalopathy (MHE) is a neuropsychiatric syndrome produced by central nervous system dysfunction subsequent to liver disease. Hyperammonemia and inflammation act synergistically to alter neurotransmission, leading to the cognitive and motor alterations in MHE, which are reproduced in rat models of chronic hyperammonemia. Patients with MHE show altered functional connectivity in different neural networks and a reduced response in the cognitive potential mismatch negativity (MMN), which correlates with attention deficits. The mechanisms by which MMN is altered in MHE remain unknown. The objectives of this work are as follows: To assess if rats with chronic hyperammonemia reproduce the reduced response in the MMN found in patients with MHE.Analyze the functional connectivity between the areas (CA1 area of the dorsal hippocampus, prelimbic cortex, primary auditory cortex, and central inferior colliculus) involved in the generation of the MMN and its possible alterations in hyperammonemia. Granger causality analysis has been applied to detect the net flow of information between the population neuronal activities recorded from a local field potential approach.Analyze if altered MMN response in hyperammonemia is associated with alterations in glutamatergic and GABAergic neurotransmission. Extracellular levels of the neurotransmitters and/or membrane expression of their receptors have been analyzed after the tissue isolation of the four target sites. The results show that rats with chronic hyperammonemia show reduced MMN response in hippocampus, mimicking the reduced MMN response of patients with MHE. This is associated with altered functional connectivity between the areas involved in the generation of the MMN. Hyperammonemia also alters membrane expression of glutamate and GABA receptors in hippocampus and reduces the changes in extracellular GABA and glutamate induced by the MMN paradigm of auditory stimulus in hippocampus of control rats. The changes in glutamatergic and GABAergic neurotransmission and in functional connectivity between the brain areas analyzed would contribute to the impairment of the MMN response in rats with hyperammonemia and, likely, also in patients with MHE. [ABSTRACT FROM AUTHOR]

High‐mobility group box‐1 (HMGB‐1) acts as a pro‐inflammatory cytokine contributing to the occurrence of many central inflammatory and infectious disorders. Brain mast cells (MCs) are the first responders to peripheral inflammatory stimulation because of their rapid response to external stimuli coupled with their release of preformed and newly synthesized reactive chemicals. Little is known about the involvement of brain MCs in the pro‐inflammatory effects of HMGB‐1 on the central nervous system (CNS). Thus, we investigated the activation process of MCs by HMGB‐1 and explored whether this process is involved in the pro‐inflammatory effects of HMGB‐1 on the CNS. In this study, we used P815 cells to study the activating role of HMGB‐1 on MCs and to explore its potential mechanism in vitro. In an in vivo study, adult male Sprague‐Dawley rats received i.c.v. injection of sterile saline or cromoglycate (stabilizer of MCs) 30 min prior to i.p. injection of HMGB‐1. Increased levels of tumor necrosis factor and IL‐1β were observed in the P815 cells, as well as in the rats' brains, after HMGB‐1 treatment. Pretreatment with the receptor of advanced glycation endproducts (RAGE)‐siRNA inhibited the HMGB‐1‐induced inflammatory process in the P815 cells. Activation of the RAGE/nuclear factor‐κB (NF‐κB) pathway was observed in both the P815 cells and rats' brains. In addition, HMGB‐1 induced the accumulation of brain MCs in the hippocampal CA1 region, and the blood–brain barrier was disrupted. Pretreatment with cromoglycate, a stabilizer of MCs, mitigated these HMGB‐1‐induced pro‐inflammatory processes in rats. These findings indicate that brain MCs are involved in the pro‐inflammatory effect of HMGB‐1 on the CNS, probably via activating the RAGE/NF‐κB pathway. [ABSTRACT FROM AUTHOR]

Accurate, reliable, and objective biomarkers for Alzheimer's disease (AD), Parkinson's disease (PD), and related age‐associated neurodegenerative disorders are urgently needed to assist in both diagnosis, particularly at early stages, and monitoring of disease progression. Technological advancements in protein detection platforms over the last few decades have resulted in a plethora of reported molecular biomarker candidates for both AD and PD; however, very few of these candidates are developed beyond the discovery phase of the biomarker development pipeline, a reflection of the current bottleneck within the field. In this review, the expanded use of selected reaction monitoring (SRM) targeted mass spectrometry will be discussed in detail as a platform for systematic verification of large panels of protein biomarker candidates prior to costly validation testing. We also advocate for the coupling of discovery‐based proteomics with modern targeted MS‐based approaches (e.g., SRM) within a single study in future workflows to expedite biomarker development and validation for AD and PD. It is our hope that improving the efficiency within the biomarker development process by use of an SRM pipeline may ultimately hasten the development of biomarkers that both decrease misdiagnosis of AD and PD and ultimately lead to detection at early stages of disease and objective assessment of disease progression. This article is part of the special issue "Proteomics". [ABSTRACT FROM AUTHOR]

Oligodendrocytes (OLs) are myelinating cells of the central nervous system. Recent studies have shown that mechanical factors influence various cell properties. Mechanical stimulation can be transduced into intracellular biochemical signals through mechanosensors, such as integrin, p130Cas, talin and vinculin. However, the molecular mechanisms underlying the mechanical regulation of OLs by mechanosensors remain largely unknown. We found that morphology of OL was affected by knockdown of the mechanosensors p130Cas or talin1. Stretching of OL precursor cells induced the phosphorylation of p130Cas and talin‐associated assembly of vinculin. Shear stress decreased the number of OL processes, whereas these effects were mechanically suppressed by dominant‐negative (DN) p130Cas, but not by DN‐talin1. To investigate the roles of p130Cas in post‐natal OLs in vivo, we constructed a novel p130Cas knock‐in mouse and found overexpression of p130Cas in vivo affected the number of mature OLs in the cortex. These results indicate that the mechanosensor p130Cas controls both OL morphogenesis and maturation. [ABSTRACT FROM AUTHOR]

X11/Mint 1 and X11‐like (X11L)/Mint 2 are neuronal adaptor protein to regulate trafficking and/or localization of various membrane proteins. By analyzing the localization of neuronal membrane proteins in X11‐, X11L‐, and X11/X11L doubly deficient mice with membrane fractionation procedures, we found that deficient of X11 and X11L decreased the level of glutamate receptors in non‐PSD fraction. This finding suggests that X11 and X11L regulate the glutamate receptor micro‐localization to the extrasynaptic region. In vitro coimmunoprecipitation studies of NMDA receptors lacking various cytoplasmic regions with X11 and X11L proteins harboring domain deletion suggest that extrasynaptic localization of NMDA receptor may be as a result of the multiple interactions of the receptor subunits with X11 and X11L regulated by protein phosphorylation, while that of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor subunits is not dependent on the binding with X11 and X11L proteins. Because the loss of X11 and X11L tends to impair the exocytosis, but not endocytosis, of glutamate receptors, NMDA receptors are likely to be supplied to the extrasynaptic plasma membrane with a way distinct from the mechanism regulating the localization of NMDA receptors into synaptic membrane region. Reduced localization of NMDA receptor into the extrasynaptic region increased slightly the phosphorylation level of cAMP responsible element binding protein in brain of X11/X11L doubly deficient mice compare to wild‐type mice, suggesting a possible role of X11 and X11L in the regulation of signal transduction pathway through extrasynaptic glutamate receptors. Open science badges: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. X11 and X11L are neuronal adaptor protein to regulate trafficking and localization of various membrane proteins, but their functions remain controversial for glutamate receptors. We found that deficient of X11 and X11L decreased the level of NMDA receptors at extrasynaptic region. X11 and X11L associate NMDA receptors through their multiple interactions and the association is regulated by protein phosphorylation. This mechanism is thought to be distinct from the mechanism regulating the localization of NMDA receptors into synaptic membrane region. Because the level of extrasynaptic NMDA receptors influences in the proapoptotic signal transduction, our finding will contribute for understanding neurodegenerative disorders. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ [ABSTRACT FROM AUTHOR]

In the central nervous system, astrocytes extend endfoot processes to ensheath synapses and microvessels. However, the mechanisms underlying this astrocytic process extension remain unclear. A limitation of the use of 2D cultured astrocytes for such studies is that they display a flat, epithelioid morphology, with no or very few processes, which is markedly different from the stellate morphology observed in vivo. In this study, we obtained 2D cultured astrocytes with a rich complexity of processes using differentiation of neurospheres in vitro. Using these process‐bearing astrocytes, we showed that laminin, an extracellular matrix molecule abundant in perivascular sites, efficiently induced process formation and branching. Specifically, the numbers of the first‐ and second‐order branch processes and the maximal process length of astrocytes were increased when cultured on laminin, compared with when they were cultured on poly‐L‐ornithine or type IV collagen. Knockdown of dystroglycan or α‐syntrophin, constituent proteins of the dystrophin–glycoprotein complex that provides a link between laminin and the cytoskeleton, using small interference RNAs inhibited astrocyte process formation and branching, and down‐regulated expression of the water channel aquaporin‐4 (AQP4). Direct knockdown and a specific inhibitor of AQP4 also inhibited, whereas over‐expression of AQP4 enhanced astrocyte process formation and branching. Knockdown of AQP4 decreased phosphorylation of focal adhesion kinase (FAK) that is critically implicated in actin remodeling. Collectively, these results indicate that the laminin–dystroglycan–α‐syntrophin–AQP4 axis is important for process formation and branching of 2D cultured astrocytes. Open Practices: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Read the Editorial Highlight for this article on page 436. Proposed model of laminin‐enhanced astrocytic process formation. Laminin interacts with dystroglycan (DG), which indirectly interacts with α‐syntrophin (Syn) through Dp71 and α‐dystrobrevin‐1 (DB). Signals from DG and Syn regulate aquaporin‐4 (AQP4) mRNA expression, and AQP4 that is anchored by Syn, regulates phosphorylation of focal adhesion kinase (FAK). Thus, laminin enhanced astrocytic process formation through the DG–Syn–AQP4 axis. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ Read the Editorial Highlight for this article on page 436. [ABSTRACT FROM AUTHOR]

The article presents abstracts of research papers related to cell death in the central nervous system. The papers were presented at a meeting of the International Society for Neurochemistry and the American Society for Neurochemistry. The abstracts include "Mitochondrial dysfunction in glial cell death," "Mitochondria, calcium and neuronal cell death," and "Confocal microscopy of cell death: shared mitochondrial pathways to apoptosis and necrosis."

The article presents an abstract of the medical research paper "Gene Transfer in CNS," which will be discussed in the Seventeenth Biennial Meeting of the International Society for Neurochemistry and the Thirteenth General Meeting of the European Society for Neurochemistry, to be held during August 8-14, 1999 in Berlin, Germany. The paper demonstrates the improved efficacy of gene transfer via cationic cholesterol-containing liposomes in the central nervous system of a rat.

The article provides information on an abstract of the paper "Analysis of Migration and Differentiation of Mouse Hindbrain Oligodendrocyte Progenitor Cells in Flat Culture System," which will be presented at the 30th meeting of the American Society for Neurochemistry from March 14-17, 1999 in Louisiana. The paper findings highlight that oligodendrocytes are the myelinating cells in the central nervous system of a human body.

The article provides information on an abstract of the paper "Intracranial Injection of Apotransferrin Causes Early Oligodendroglial Cell Differentiation and Downregulates the Expression of Its Gene in the CNS," which will be presented at the 30th meeting of the American Society for Neurochemistry in Louisiana. The paper findings highlight that oligodendrocytes and the myelin forming cells are also responsible in the central nervous system for the synthesis of transferrin.

The article presents an abstract of the paper "B7-1 Expression by Oligodendrocytes Enhances Viral-Induced CNS Autoimmune Disease," which will be presented at the 30th Annual Meeting of the American Society for Neurochemistry to be held from March 14-17, 1999 in New Orleans, Louisiana. The paper focuses on how the central nervous system autoimmune disease can get effected by infection on a virus sharing epitopes along with a protein delivered in oligodendrocytes.

The article presents an abstract of the paper "Formation of Advanced Glycation End Products by Human Proteolipid Protein," which will be presented at the 30th Annual Meeting of the American Society for Neurochemistry to be held from March 14-17, 1999 in New Orleans, Louisiana. Proteolipid was found to be a target protein for glycation and advanced glycation end products formation in the brain in the paper and it can be engaged in the central nervous system pathophysiology in diabetes.

The article presents an abstract of the paper "Nicotine Induced Changes in Gene Expression in the Central Nervous System," which will be presented at the 30th annual meeting of the American Society for Neurochemistry to be held from March 14-17, 1999 in New Orleans, Louisiana. The paper discusses the changes in gene expression associated with addiction to nicotine in the central nervous system.

The endocannabinoid system shifts energy balance toward storage and fat accumulation, especially in the context of diet-induced obesity. Relatively little is known about factors outside the central nervous system that may mediate the effect of high-fat diet ( HFD) on brain endocannabinoid levels. One candidate is the liver fatty acid binding protein ( FABP1), a cytosolic protein highly prevalent in liver, but not detected in brain, which facilitates hepatic clearance of fatty acids. The impact of Fabp1 gene ablation ( LKO) on the effect of high-fat diet ( HFD) on brain and plasma endocannabinoid levels was examined and data expressed for each parameter as the ratio of high-fat diet/control diet. In male wild-type mice, HFD markedly increased brain N-acylethanolamides, but not 2-monoacylglycerols. LKO blocked these effects of HFD in male mice. In female wild-type mice, HFD slightly decreased or did not alter these endocannabinoids as compared with male wild type. LKO did not block the HFD effects in female mice. The HFD-induced increase in brain arachidonic acid-derived arachidonoylethanolamide in males correlated with increased brain-free and total arachidonic acid. The ability of LKO to block the HFD-induced increase in brain arachidonoylethanolamide correlated with reduced ability of HFD to increase brain-free and total arachidonic acid in males. In females, brain-free and total arachidonic acid levels were much less affected by either HFD or LKO in the context of HFD. These data showed that LKO markedly diminished the impact of HFD on brain endocannabinoid levels, especially in male mice. [ABSTRACT FROM AUTHOR]

The central nervous system and viscera constitute a functional ensemble, the gut-brain axis, that allows bidirectional information flow that contributes to the control of feeding behavior based not only on the homeostatic, but also on the hedonic aspects of food intake. The prevalence of eating disorders, such as anorexia nervosa, binge eating and obesity, poses an enormous clinical burden, and involves an ever-growing percentage of the population worldwide. Clinical and preclinical research is constantly adding new information to the field and orienting further studies with the aim of providing a foundation for developing more specific and effective treatment approaches to pathological conditions. A recent symposium at the XVI Congress of the Societá Italiana di Neuroscienze (SINS, 2015) 'Eating disorders: from bench to bedside and back' brought together basic scientists and clinicians with the objective of presenting novel perspectives in the neurobiology of eating disorders. Clinical studies presented by V. Ricca illustrated some genetic aspects of the psychopathology of anorexia nervosa. Preclinical studies addressed different issues ranging from the description of animal models that mimic human pathologies such as anorexia nervosa, diet-induced obesity, and binge eating disorders (T. Lutz), to novel interactions between peripheral signals and central circuits that govern food intake, mood and stress (A. Romano and G. Provensi). The gut-brain axis has received increasing attention in the recent years as preclinical studies are demonstrating that the brain and visceral organs such as the liver and guts, but also the microbiota are constantly engaged in processes of reciprocal communication, with unexpected physiological and pathological implications. Eating is controlled by a plethora of factors; genetic predisposition, early life adverse conditions, peripheral gastrointestinal hormones that act directly or indirectly on the central nervous system, all are receiving attention as they presumably contribute to the development of eating disorders. [ABSTRACT FROM AUTHOR]

The article presents abstracts of research papers about blood brain barrier and its role in immune privilege in the CNS in health and disease. They include "Heterogeneity of the CNS microvasculature," "Reactive oxygen species and pathological events in multiple sclerosis," "Dendritic cell migration across the blood-brain barrier is mediated via tight junctions in mmp-dependent way," and "Blood-brain barrier transmigration of human monocytes induces their differentiation into dendritic cells."

The article presents abstracts of research papers about molecular and cellular mechanisms of migration during central nervous system myelination and remyelination. They include "Complex origins of oligodendrocytes in the forebrain," "Environmental regulation of oligodendrocyte precursor development," "Molecular control of neural stem cell mobilization in the demyelinated CNS," and "Oligodendrogenesis in an NG2-reactive zone after spinal cord injury."

The article presents abstracts of research papers about the role of manganese in central nervous system neurotoxicity and idiopathic Parkinson's disease. They include "Manganese-induced dopamine neurodegeneration in C. elegans: pharmacogenetic analysis in a novel model of manganism," "Dietary iron modulates manganese neurotoxicity," "Effects of chronic manganese exposure on cognitive and motor functioning in nonhuman primates," and "Neuroimaging and neuropathological changes in the nonhuman primate brain by chronic Mn exposure."

The long-term effects and action mechanisms of subthalamic nucleus ( STN) high-frequency stimulation ( HFS) for Parkinson's disease still remain poorly characterized, mainly due to the lack of experimental models relevant to clinical application. To address this issue, we performed a multilevel study in freely moving hemiparkinsonian rats undergoing 5-week chronic STN HFS, using a portable constant-current microstimulator. In vivo metabolic neuroimaging by 1H-magnetic resonance spectroscopy (11.7 T) showed that STN HFS normalized the tissue levels of the neurotransmission-related metabolites glutamate, glutamine and GABA in both the striatum and substantia nigra reticulata ( SNr), which were significantly increased in hemiparkinsonian rats, but further decreased nigral GABA levels below control values; taurine levels, which were not affected in hemiparkinsonian rats, were significantly reduced. Slice electrophysiological recordings revealed that STN HFS was, uniquely among antiparkinsonian treatments, able to restore both forms of corticostriatal synaptic plasticity, i.e. long-term depression and potentiation, which were impaired in hemiparkinsonian rats. Behavior analysis (staircase test) showed a progressive recovery of motor skill during the stimulation period. Altogether, these data show that chronic STN HFS efficiently counteracts metabolic and synaptic defects due to dopaminergic lesion in both the striatum and SNr. Comparison of chronic STN HFS with acute and subchronic treatment further suggests that the long-term benefits of this treatment rely both on the maintenance of acute effects and on delayed actions on the basal ganglia network. [ABSTRACT FROM AUTHOR]

Calcitonin gene-related peptide ( CGRP) is a 37 amino acid neuropeptide, which plays a critical role in the central nervous system. CGRP binds to G protein-coupled receptors, including CGRP1, which couples positively to adenylyl cyclase ( AC) and protein kinase A ( PKA) activation. CGRP and CGRP1 receptors are enriched in central nucleus of the amygdala (CeA), the main part of the amygdala, which regulates conditioned fear memories. Here, we reported the importance of CGRP and CGRP1 receptor for synaptic plasticity in the CeA and the extinction of fear memory in rats. Our electrophysiological and behavioral in vitro and in vivo results showed exogenous application of CGRP induced an immediate and lasting long-term potentiation in the basolateral nucleus of amygdala-CeA pathway, but not in the lateral nucleus of amygdala-CeA pathway, while bilateral intra-CeA infusion CGRP (0, 5, 13 and 21 μM/side) dose dependently enhanced fear memory extinction. The effects were blocked by CGRP1 receptor antagonist ( CGRP8-37), N-methyl- d-aspartate receptors antagonist MK801 and PKA inhibitor H89. These results demonstrate that CGRP can lead to long-term potentiation of basolateral nucleus of amygdala-CeA pathway through a PKA-dependent postsynaptic mechanism that involved N-methyl- d-aspartate receptors and enhance the extinction of fear memory in rats. Together, the results strongly support a pivotal role of CGRP in the synaptic plasticity of CeA and extinction of fear memory. [ABSTRACT FROM AUTHOR]

The article presents abstracts of research papers related to glutathione metabolism in the central nervous system. They include "Pathways involved in peroxide detoxification by brain cells," "Cellular and subcellular localization of glutathione and glutathione precursors: high resolution immunogold analyses," and "Impairment of energy production in brain mitochondria by glutathione deprivation and nitric oxide production."

Glutamate dehydrogenase ( GDH), encoded by GLUD1, participates in the breakdown and synthesis of glutamate, the main excitatory neurotransmitter. In the CNS, besides its primary signaling function, glutamate is also at the crossroad of metabolic and neurotransmitter pathways. Importance of brain GDH was questioned here by generation of CNS-specific GDH-null mice (Cns Glud1−/−); which were viable, fertile and without apparent behavioral problems. GDH immunoreactivity as well as enzymatic activity were absent in Cns- Glud1−/− brains. Immunohistochemical analyses on brain sections revealed that the pyramidal cells of control animals were positive for GDH, whereas the labeling was absent in hippocampal sections of Cns- Glud1−/− mice. Electrophysiological recordings showed that deletion of GDH within the CNS did not alter synaptic transmission in standard conditions. Cns- Glud1−/− mice exhibited deficient oxidative catabolism of glutamate in astrocytes, showing that GDH is required for Krebs cycle pathway. As revealed by NMR studies, brain glutamate levels remained unchanged, whereas glutamine levels were increased. This pattern was favored by up-regulation of astrocyte-type glutamate and glutamine transporters and of glutamine synthetase. Present data show that the lack of GDH in the CNS modifies the metabolic handling of glutamate without altering synaptic transmission. [ABSTRACT FROM AUTHOR]

Successful axonal regeneration is a complex process determined by both axonal environment and endogenous neural capability of the regenerating axons in the central and the peripheral nervous systems. Numerous external inhibitory factors inhibit axonal regeneration after injury. In response, neurons express various regeneration-associated genes to overcome this inhibition and increase the intrinsic growth capacity. In the present study, we show that the brainexpressed X-linked (Bex1) protein was over-expressed as a result of peripheral axonal damage. Bex1 antagonized the axon outgrowth inhibitory effect of myelin-associated glycoprotein. The involvement of Bex1 in axon regeneration was further confirmed in vivo. We have demonstrated that Bex1 knock-out mice showed lower capability for regeneration after peripheral nerve injury than wild-type animals. Wild-type mice could recover from sciatic nerve injury much faster than Bex1 knock-out mice. Our findings suggest that Bex1 could be considered as regeneration-associated gene. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 113, 930–942. Granulocyte-colony stimulating factor (G-CSF) is a potent hematopoietic factor that drives differentiation of neutrophilic granulocytes. We have recently shown that G-CSF also acts as a neuronal growth factor, protects neurons in vitro and in vivo, and has regenerative potential in various neurological disease models. Spinal cord injury (SCI) following trauma or secondary to skeletal instability is a terrible condition with no effective therapies available at present. In this study, we show that the G-CSF receptor is up-regulated upon experimental SCI and that G-CSF improves functional outcome in a partial dissection model of SCI. G-CSF significantly decreases apoptosis in an experimental partial spinal transsection model in the mouse and increases expression of the anti-apoptotic G-CSF target gene Bcl-XL. In vitro, G-CSF enhances neurite outgrowth and branching capacity of hippocampal neurons. In vivo, G-CSF treatment results in improved functional connectivity of the injured spinal cord as measured by Mn2+-enhanced MRI. G-CSF also increased length of the dorsal corticospinal tract and density of serotonergic fibers cranial to the lesion center. Mice treated systemically with G-CSF as well as transgenic mice over-expressing G-CSF in the CNS exhibit a strong improvement in functional outcome as measured by the BBB score and gridwalk analysis. We show that G-CSF improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. We conclude that G-CSF constitutes a promising and feasible new therapy option for SCI. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 113, 489–501. The effect of GABA on glutamate release from astrocytes has been studied in healthy mice and in a murine transgenic model of amyotrophic lateral sclerosis (ALS), using mouse spinal cord gliosomes labeled with [3H]d-aspartate ([3H]d-ASP). GABA concentration-dependently evoked the release of [3H]d-ASP. The effect of GABA was not mimicked by GABAA or GABAB receptor agonists or counteracted by antagonists, excluding receptor involvement. However, it was prevented by the GABA transport inhibitor N-(4,4-phenyl-3-butenyl)-nipecotic acid (SKF 89976A), suggesting participation of GABA transporters type 1 (GAT1) placed on glutamate-releasing astrocyte-derived gliosomes. Accordingly, GAT1 co-expressed with glutamate–aspartate transporter (GLAST) and glutamate transporter type 1 (GLT1) in the majority of glial particles. [3H]d-aspartate release was Ca2+-independent and not blocked by the glutamate uptake inhibitordl-threo-b-benzyloxyaspartic acid (dl-TBOA); instead, it was abrogated by the anion channel blockers niflumic acid and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). The GAT1-mediated release of [3H]d-ASP was significantly enhanced in spinal cord gliosomes from the mouse model of ALS. This excessive [3H]d-ASP release was very precocious, largely preceding the onset of the disease symptoms. These data indicate that GAT1, GLAST and GLT1 coexist on the same gliosome in mouse spinal cord and that activation of GAT1 transporters elicits glutamate release by anion channel opening. This phenomenon might have pathological relevance, because [3H]d-ASP release is enhanced in experimental ALS. [ABSTRACT FROM AUTHOR]