• Alzheimer’s disease
• dementia with Lewy bodies
• epilepsy
• epileptic activity
• network hyperexcitability

• ARBs
• Ischemic stroke
• ceftriaxone
• excitotoxicity
• glutamate

• Cognitive deficits
• EAAT1
• EAAT2
• Schizophrenia
• Symptom

• arteriole diameter
• astrocyte
• glutamate transport
• in vivo microscopy
• neurovascular coupling

• R01 NS106693 NINDS NIH HHS
• U54 HD086984 NICHD NIH HHS

• EAAC1
• Excitatory amino acid transporter
• GLAST
• GLT-1
• Glutamate transport
• Protein kinase C

The physiological balance between excitation and inhibition in the brain is significantly affected in Alzheimer’s disease (AD). Several neuroactive compounds and their signaling pathways through various types of receptors are crucial in brain homeostasis, among them glutamate and γ-aminobutyric acid (GABA). Activation of microglial receptors regulates the immunological response of these cells, which in AD could be neuroprotective or neurotoxic. The novel research approaches revealed the complexity of microglial function, including the interplay with other cells during neuroinflammation and in the AD brain. The purpose of this review is to describe the role of several proteins and multiple receptors on microglia and neurons, and their involvement in a communication network between cells that could lead to different metabolic loops and cell death/survival. Our review is focused on the role of glutamatergic, GABAergic signaling in microglia–neuronal cross-talk in AD and neuroinflammation. Moreover, the significance of AD-related neurotoxic proteins in glutamate/GABA-mediated dialogue between microglia and neurons was analyzed in search of novel targets in neuroprotection, and advanced pharmacological approaches.

• Alzheimer’s disease
• GABA
• glutamate
• microglia
• neurodegeneration
• neuroinflammation
• neurons
• neurotransmission
• signaling
• therapeutic approaches

• Alzheimer Disease/metabolism
• Amyloid beta-Peptides/metabolism
• Animals
• Brain/metabolism
• Glutamic Acid/metabolism
• Humans
• Microglia/metabolism
• Neuroinflammatory Diseases/metabolism
• Neurons/metabolism
• Receptor Cross-Talk
• gamma-Aminobutyric Acid/metabolism

Schizophrenia is a severe and clinically heterogenous mental disorder affecting approximately 1% of the population worldwide. Despite tremendous achievements in the field of schizophrenia research, its precise aetiology remains elusive. Besides dysfunctional neuronal signalling, the pathophysiology of schizophrenia appears to involve molecular and functional abnormalities in glial cells, including astrocytes. This article provides a concise overview of the current evidence supporting altered astrocyte activity in schizophrenia, which ranges from findings obtained from post-mortem immunohistochemical analyses, genetic association studies and transcriptomic investigations, as well as from experimental investigations of astrocyte functions in animal models. Integrating the existing data from these research areas strongly suggests that astrocytes have the capacity to critically affect key neurodevelopmental and homeostatic processes pertaining to schizophrenia pathogenesis, including glutamatergic signalling, synaptogenesis, synaptic pruning and myelination. The further elucidation of astrocytes functions in health and disease may, therefore, offer new insights into how these glial cells contribute to abnormal brain development and functioning underlying this debilitating mental disorder.

• Astrocytes
• glutamate hypothesis
• neurodevelopment
• schizophrenia

• Compensation
• Cysteine
• Glutathione
• Oxidative stress
• System xc(-)

Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain reward system, with lasting neurobiological consequences that potentiate subsequent consumption. Recent evidence shows that the brain displays marked oxidative stress and neuroinflammation following chronic drug consumption. Brain oxidative stress and neuroinflammation disrupt glutamate homeostasis by impairing synaptic and extra-synaptic glutamate transport, reducing GLT-1, and system X_c⁻ activities respectively, which increases glutamatergic neurotransmission. This effect consolidates the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption. Recently, promising results as experimental treatments to reduce drug consumption and relapse have been shown by (i) antioxidant and anti-inflammatory synthetic molecules whose effects reach the brain; (ii) natural biomolecules secreted by mesenchymal stem cells that excel in antioxidant and anti-inflammatory properties, delivered via non-invasive intranasal administration to animal models of drug abuse and (iii) potent anti-inflammatory microRNAs and anti-miRNAs which target the microglia and reduce neuroinflammation and drug craving. In this review, we address the neurobiological consequences of brain oxidative stress and neuroinflammation that follow the chronic consumption of most drugs of abuse, and the current and potential therapeutic effects of antioxidants and anti-inflammatory agents and biomolecules to reduce these drug-induced alterations and to prevent relapse.

• drug addiction
• neuroinflammation
• oxidative stress
• treatment

Certain cognitive deficits in schizophrenia, such as impaired working memory, are thought to reflect alterations in the neural circuitry of the dorsolateral prefrontal cortex (DLPFC). Gamma oscillations in the DLPFC appear to be a neural corollary of working memory function, and the power of these oscillations during working memory tasks is lower in individuals with schizophrenia. Thus, gamma oscillations represent a potentially useful biomarker to index dysfunction in the DLPFC circuitry responsible for working memory in schizophrenia. Postmortem studies, by identifying the cellular basis of DLPFC dysfunction, can help inform the utility of biomarker measures obtained in vivo. Given that gamma oscillations reflect network activity of excitatory pyramidal neurons and inhibitory GABA neurons, we review postmortem findings of alterations to both cell types in the DLPFC and discuss how these findings might inform future biomarker development and use.

• Cognition
• GABA
• Glutamate
• Schizophrenia
• Working memory
• gamma oscillations

• Astrocytes
• Blood-brain barrier
• Endothelia
• GLAST
• GLT-1
• Notch

Peroxisome proliferator activated receptor alpha (PPAR-α) belongs to the family of ligand-regulated nuclear receptors (PPARs). These receptors after heterodimerization with retinoid X receptor (RXR) bind in promotor of target genes to PPAR response elements (PPREs) and act as a potent transcription factors. PPAR-α and other receptors from this family, such as PPAR-β/δ and PPAR-γ are expressed in the brain and other organs and play a significant role in oxidative stress, energy homeostasis, mitochondrial fatty acids metabolism and inflammation. PPAR-α takes part in regulation of genes coding proteins that are involved in glutamate homeostasis and cholinergic/dopaminergic signaling in the brain. Moreover, PPAR-α regulates expression of genes coding enzymes engaged in amyloid precursor protein (APP) metabolism. It activates gene coding of α secretase, which is responsible for non-amyloidogenic pathway of APP degradation. It also down regulates β secretase (BACE-1), the main enzyme responsible for amyloid beta (Aβ) peptide release in Alzheimer Diseases (AD). In AD brain expression of genes of PPAR-α and PPAR-γ coactivator-1 alpha (PGC-1α) is significantly decreased. PPARs are altered not only in AD but in other neurodegenerative/neurodevelopmental and psychiatric disorder. PPAR-α downregulation may decrease anti-oxidative and anti-inflammatory processes and could be responsible for the alteration of fatty acid transport, lipid metabolism and disturbances of mitochondria function in the brain of AD patients. Specific activators of PPAR-α may be important for improvement of brain cells metabolism and cognitive function in neurodegenerative and neurodevelopmental disorders.

• App/aβ metabolism
• Glutamatergic signaling
• Mitochondria function
• Neurodegeneration
• Neuroprotection
• PPAR-α

Adenosine receptors A1 (A1AR) and A2a (A2aAR) play an important role in regulating glutamate uptake to avoid glutamate accumulation that causes excitotoxicity in the brain; however, the precise mechanism of the effects of A1AR and A2aAR is unclear. Herein, we report that expression of the A1AR protein in the astrocyte membrane and the level of intracellular glutamate were decreased, while expression of the A2aR protein was elevated in cells exposed to oxygen-glucose deprivation (OGD) conditions. Coimmunoprecipitation (Co-IP) experiments showed that A1AR interacts with A2aAR under OGD conditions. The activation of A1AR and inactivation of A2aAR by 2-chloro-N6-cyclopentyladenosine (CCPA) and SCH58251, respectively, partly reversed OGD-mediated glutamate uptake dysfunction, elevated EAAT2, and PPARγ protein levels, and suppressed the expression of Ying Yang 1 (YY1). Both the silencing of YY1 and the activation of PPARγ upregulated EAAT2 expression. Moreover, YY1 silencing elevated the PPARγ level under both normal and OGD conditions. Histone deacetylase (HDAC)1 was found to interact with YY1, and HDAC1 silencing improved PPARγ promoter activity. Taken together, our findings suggest that A1AR-A2aAR heteromers regulate EAAT2 expression and glutamate uptake through the YY1-mediated recruitment of HDAC1 to the PPARγ promoter region.

• Astrocyte
• Calcium
• Glutamate transport
• Metabolism
• Mitochondria
• Sodium

• Amino Acid Transport System X-AG/metabolism
• Animals
• Astrocytes/metabolism
• Cell Communication
• Glutamic Acid/metabolism
• Humans
• Mitochondria/metabolism
• Neurons/metabolism
• Signal Transduction

• R01 NS106693 NINDS NIH HHS

• Cerebral ischemia
• Expression
• Glutamate transporter
• Reversal
• Trafficking

Glutamate is the predominant excitatory neurotransmitter in the human brain and it has been shown that prolonged activation of the glutamatergic system leads to nerve damage and cell death. Following release from the pre-synaptic neuron and synaptic transmission, glutamate is either taken up into the pre-synaptic neuron or neighbouring glia by transmembrane glutamate transporters. Excitatory amino acid transporter (EAAT) 1 and EAAT2 are Na⁺-dependant glutamate transporters expressed predominantly in glia cells of the central nervous system. As the most abundant glutamate transporters, their primary role is to modulate levels of glutamatergic excitability and prevent spill over of glutamate beyond the synapse. This role is facilitated through the binding and transportation of glutamate into astrocytes and microglia. The function of EAAT1 and EAAT2 is heavily regulated at the levels of gene expression, post-transcriptional splicing, glycosylation states and cell-surface trafficking of the protein. Both glutamatergic dysfunction and glial dysfunction have been proposed to be involved in psychiatric disorder. This review will present an overview of the roles that EAAT1 and EAAT2 play in modulating glutamatergic activity in the human brain, and mount an argument that these two transporters could be involved in the aetiologies of schizophrenia and affective disorders as well as represent potential drug targets for novel therapies for those disorders.

• Glia
• Excitatory amino acid transporter
• Psychiatry
• Affective disorders
• Glutamate transporter
• Glutamate
• Schizophrenia

Neuronal hyperactivity is one of the earliest events observed in Alzheimer’s disease (AD). Moreover, alterations in the expression of glutamate transporters have been reported to exacerbate amyloid pathology and cognitive deficits in transgenic AD mouse models. However, the molecular links between these pathophysiological changes remain largely unknown. Here, we report novel interaction between presenilin 1 (PS1), the catalytic component of the amyloid precursor protein-processing enzyme, γ-secretase, and a major glutamate transporter-1 (GLT-1). Our data demonstrate that the interaction occurs between PS1 and GLT-1 expressed at their endogenous levels in vivo and in vitro, takes place in both neurons and astrocytes, and is independent of the PS1 autoproteolysis and γ-secretase activity. This intriguing discovery may shed light on the molecular crosstalk between the proteins linked to the maintenance of glutamate homeostasis and Aβ pathology.

• Inflammation
• Nrf2
• Remyelination
• Stroke
• Thiazolidinedione
• Traumatic brain injury

• GLT-1
• Notch
• astrocytes
• blood-brain barrier
• endothelial cells
• transcription

• GLT-1
• Notch
• astrocytes
• blood-brain barrier
• endothelial cells
• transcription

• Aquaporin 4
• Astrocyte
• Glutamate transporter 1
• Macromolecular complex
• Mu opioid receptor
• Protein kinase C

• Astrocytes
• Endocytosis
• Glutamate transporter-1
• PPAR-alpha
• Protein kinase C

• Alzheimer’s disease
• Calcium
• TRPC6
• β-amyloid

Astrocytes are the most abundant neuron-supporting glial cells in the central nervous system. The neuroprotective role of astrocytes has been demonstrated in various neurological disorders such as amyotrophic lateral sclerosis, spinal cord injury, stroke and Parkinson’s disease (PD). Astrocyte dysfunction or loss-of-astrocytes increases the susceptibility of neurons to cell death, while astrocyte transplantation in animal studies has therapeutic advantage. We reported recently that stimulation of serotonin 1A (5-HT_1A) receptors on astrocytes promoted astrocyte proliferation and upregulated antioxidative molecules to act as a neuroprotectant in parkinsonian mice. PD is a progressive neurodegenerative disease with motor symptoms such as tremor, bradykinesia, rigidity and postural instability, that are based on selective loss of nigrostriatal dopaminergic neurons, and with non-motor symptoms such as orthostatic hypotension and constipation based on peripheral neurodegeneration. Although dopaminergic therapy for managing the motor disability associated with PD is being assessed at present, the main challenge remains the development of neuroprotective or disease-modifying treatments. Therefore, it is desirable to find treatments that can reduce the progression of dopaminergic cell death. In this article, we summarize first the neuroprotective properties of astrocytes targeting certain molecules related to PD. Next, we review neuroprotective effects induced by stimulation of 5-HT_1A receptors on astrocytes. The review discusses new promising therapeutic strategies based on neuroprotection against oxidative stress and prevention of dopaminergic neurodegeneration.

It has become well accepted that Huntington disease (HD) is associated with impaired glutamate uptake, resulting in a prolonged time-course of extracellular glutamate that contributes to excitotoxicity. However, the data supporting this view come largely from work in synaptosomes, which may overrepresent nerve-terminal uptake over astrocytic uptake. Here, we quantify real-time glutamate dynamics in HD mouse models by high-speed imaging of an intensity-based glutamate-sensing fluorescent reporter (iGluSnFR) and electrophysiological recordings of synaptically activated transporter currents in astrocytes. These techniques reveal a disconnect between the results obtained in synaptosomes and those in situ. Exogenous glutamate uptake is impaired in synaptosomes, whereas real-time measures of glutamate clearance in the HD striatum are normal or even accelerated, particularly in the aggressive R6/2 model. Our results highlight the importance of quantifying glutamate dynamics under endogenous release conditions, and suggest that the widely cited uptake impairment in HD does not contribute to pathogenesis.

Huntington disease (HD) has been linked via biochemical uptake assays to impaired glutamate clearance and resultant excitotoxicity. Here, utilizing a fluorescent reporter, the authors measure real-time glutamate dynamics in mouse model HD brain slices and find normal or even accelerated glutamate clearance.

• Astrocytes
• EAAC1
• EAAT
• GLAST
• GLT-1
• Glu uptake
• Transcriptional regulation

• ATP-Binding Cassette Transporters/metabolism
• Amino Acid Transport System X-AG/metabolism
• Animals
• Astrocytes/metabolism
• Glutamic Acid/metabolism
• Humans
• Neurons/metabolism
• Signal Transduction
• Transcription Factors/metabolism

• R01 NS092067 NINDS NIH HHS

• EAAT
• GLAST
• GLT-1
• Glutamate transport
• Glycogen
• Glycolysis
• Mitochondria

• Alzheimer's disease
• NFκB
• astrocytes
• complement
• microglia
• neuron-glia interaction

• Alzheimer Disease/metabolism
• Alzheimer Disease/pathology
• Animals
• Cell Communication
• Central Nervous System/pathology
• Humans
• Models, Biological
• Neuroglia/physiology
• Neurons/physiology
• Signal Transduction/physiology

• AG020670 NIA NIH HHS
• R01 NS076117 NINDS NIH HHS
• R01 AG020670 NIA NIH HHS
• AG032051 NIA NIH HHS
• R01 AG032051 NIA NIH HHS
• RF1 AG020670 NIA NIH HHS
• NS076117 NINDS NIH HHS

• Astrocytes
• Endogenous analgesia
• Glutamate transporter-1
• Locus coeruleus
• Small interfering RNA

• Buyang Huanwu decoction
• astrocyte
• focal cerebral ischemia
• glutamate transporter-1
• glutamine synthetase
• pituitary adenylate cyclase-activating polypeptide-38

• Coupling/uncoupling
• Glutamate transporter
• Glutamate uptake
• Interaction
• Na+, K+-ATPase

• Alcohol
• frontal cortex
• glutamate transporter
• glutamate uptake
• hippocampus
• postnatal stress

• Alcohol Drinking/metabolism
• Alcohol Drinking/psychology
• Animals
• Brain/metabolism
• Central Nervous System Depressants/administration & dosage
• Chronic Disease
• Cold Temperature
• Ethanol/administration & dosage
• Excitatory Amino Acid Transporter 1/metabolism
• Excitatory Amino Acid Transporter 2/metabolism
• Excitatory Amino Acid Transporter 3/metabolism
• Frontal Lobe/metabolism
• Glutamic Acid/metabolism
• Hippocampus/metabolism
• Male
• Maternal Deprivation
• Rats
• Rats, Wistar
• Self Administration/psychology
• Stress, Psychological/metabolism
• Stress, Psychological/psychology

• glutamate transporter
• hexokinase
• mitochondria

• EAAT
• brain tissue
• glutamate receptors
• glutamatergic neurons
• schizophrenia

• Excitotoxicity
• GLT-1
• Glutamate
• Neurological disorders

• EAAT2
• GLT1
• P rats
• alcohol dependence
• glutamate