Metabotropic glutamate receptors(mGluRs)in epileptogenesis:an update on abnormal mGluRs signaling and its therapeutic implications

Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug resistance.Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy.Metabotropic glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic plasticity.Dysregulated mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of epilepsy.In this review,we first introduce the three groups of mGluRs and their associated signaling pathways.Then,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in epileptogenesis.In addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also summarized.We hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.

Temporal and spatial distribution of metabotropic glutamate receptor 5 during development in the rat cortex and hippocampus

Metabotropic glutamate receptor 5 （mGluR5） is expressed by neurons in zones of active neurogenesis and is involved in the development of neural stem cells in vivo and in vitro. We examined the expression of mGluR5 in the cortex and hippocampus of rats during various prenatal and postnatal periods using immunohistochemistry. During prenatal development, mGluR5 was pdmadly localized to neuronal somas in the forebrain. During early postnatal periods, the receptor was mainly present on somas in the cortex, mGluR5 immunostaining was visible in apical dendrites and in the neuropil of neurons and persisted throughout postnatal development. During this period, pyramidal neurons were strongly labeled for the receptor. In the hippocampal CA1 region, mGluR5 immunoreactivity was more intense in the stratum oriens, stratum radiatum, and lacunosum moleculare at P0, P5 and P10 relative to P60. mGluR5 expression increased significantly in the molecular layer and decreased significantly in the granule cell layer of the dentate gyrus at P5, P10 and P60 in comparison with P0. Furthermore, some mGluR5-positive cells were also bromodeoxyuridine- or NeuroD-positive in the dentate gyrus at P14. These results demonstrate that mGluR5 has a differential expression pattern in the cortex and hippocampus during early growth, suggesting a role for this receptor in the control of domain specific brain developmental events.

Expression of metabotropic glutamate receptor 1a in a rat cortical neuronal model of in vitro mechanical injury and the effects of its competitive antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid

The present study established a rat cortical neuronal model of in vitro mechanical injury. At 30 minutes after injury, the survival rate of the injured cortical neurons was decreased compared with normal neurons, and was gradually decreased with aggravated degree of injury. Reverse transcription-polymerase chain reaction results showed that at 1 hour after injury, there was increased expression of metabotropic glutamate receptor la in cortical neurons. Immunohistochemical staining results showed that at 30 minutes after injury, the number of metabotropic glutamate receptor 1a-positive cells increased compared with normal neurons. At 12 hours after injury, lactate dehydrogenase activity in the （RS）-l-aminoindan-1, 5-dicarboxylic acid （AIDA）-treated injury neurons was si[jnificantly decreased than that in the pure injury group. At 1 hour after injury, intracellular free Ca＂＋ concentration was markedly decreased in the AIDA-treated injury neurons than that in the pure injury neurons. These findings suggest that after mechanical injury to cortical neurons, metabotropic glutamate receptor la expression increased. The resulting increase in intracellular free Ca2＋ concentration was blocked by AIDA, indicating that AIDA exhibits neuroprotective effects after mechanical injury.

Altered expression of metabotropic glutamate receptor 1 alpha after acute diffuse brain injury Effect of the competitive antagonist 1-aminoindan-1, 5-dicarboxylic acid

The diffuse brain injury model was conducted in Sprague-Dawley rats, according to Marmarou＇s free-fall attack. The water content in brain tissue, expression of metabotropic glutamate receptor la mRNA and protein were significantly increased after injury, reached a peak at 24 hours, and then gradually decreased. After treatment with the competitive antagonist of metabotropic glutamate receptor la, （RS）-l-aminoindan-1,5-dicarboxylic acid, the water content of brain tissues decreased between 12-72 hours after injury, and neurological behaviors improved at 2 weeks. These experimental findings suggest that the 1-aminoindan-1, 5-dicarboxylic acid may result in marked neuroprotection against diffuse brain injury.

Metabotropic glutamate receptors and nitric oxide in dopaminergic neurotoxicity

Dopaminergic neurotoxicity is characterized by damage and death of dopaminergic neurons.Parkinson's disease(PD)is a neurodegenerative disorder that primarily involves the loss of dopaminergic neurons in the substantia nigra.Therefore,the study of the mechanisms,as well as the search for new targets for the prevention and treatment of neurodegenerative diseases,is an important focus of modern neuroscience.PD is primarily caused by dysfunction of dopaminergic neurons;however,other neurotransmitter systems are also involved.Research reports have indicated that the glutamatergic system is involved in different pathological conditions,including dopaminergic neurotoxicity.Over the last two decades,the important functional interplay between dopaminergic and glutamatergic systems has stimulated interest in the possible role of metabotropic glutamate receptors(mGluRs)in the development of extrapyramidal disorders.However,the specific mechanisms driving these processes are presently unclear.The participation of the universal neuronal messenger nitric oxide(NO)in the mechanisms of dopaminergic neurotoxicity has attracted increased attention.The current paper aims to review the involvement of mGluRs and the contribution of NO to dopaminergic neurotoxicity.More precisely,we focused on studies conducted on the rotenone-induced PD model.This review is also an outline of our own results obtained using the method of electron paramagnetic resonance,which allows quantitation of NO radicals in brain structures.

GroupⅢmetabotropic glutamate receptors and drug addiction

Neuroadaptations of glutamatergic transmission in the limbic reward circuitry are linked to persistent drug addiction.Accumulating data have demonstrated roles of ionotropic glutamate receptors and groupⅠandⅡmetabotropic glutamate receptors(mGluRs)in this event.Emerging evidence also identifies Gαi/o-coupled groupⅢmGluRs(mGluR4/7/8 subtypes enriched in the limbic system)as direct substrates of drugs of abuse and active regulators of drug action.Auto-and heteroreceptors of mGluR4/7/8 reside predominantly on nerve terminals of glutamatergic corticostriatal and GABAergic striatopallidal pathways,respectively.These presynaptic receptors regulate basal and/or phasic release of respective transmitters to maintain basal ganglia homeostasis.In response to operant administration of common addictive drugs,such as psychostimulants(cocaine and amphetamine),alcohol and opiates,limbic groupⅢmGluRs undergo drastic adaptations to contribute to the enduring remodeling of excitatory synapses and to usually suppress drug seeking behavior.As a result,a loss-of-function mutation(knockout)of individual groupⅢreceptor subtypes often promotes drug seeking.This review summarizes the data from recent studies on three groupⅢreceptor subtypes(mGluR4/7/8)expressed in the basal ganglia and analyzes their roles in the regulation of dopamine and glutamate signaling in the striatum and their participation in the addictive properties of three major classes of drugs(psychostimulants,alcohol,and opiates).

Developmental distribution pattern of metabotropic glutamate receptor 5 in prenatal human hippocampus

Objective Metabotropic glutamate receptor 5 （mGluR5） is concentrated in zones of active neurogenesis in the prenatal and postnatal rodent brain and plays an important role in the regulation of neurogenesis. However, little is known about mGluR5 in the prenatal human brain. Here, we aimed to explore the expression pattern and cellular distribution of mGluR5 in human fetal hippocampus. Methods Thirty-four human fetuses were divided into four groups according to gestational age： 9-11, 14-16, 22-24 and 32-36 weeks. The hippocampus was dissected out and prepared. The protein and mRNA expression of mGluR5 were evaluated by Western blot and immunohistochemistry or real-time PCR. The cellular distribution of mGluR5 was observed with double-labeling immunofluorescence. Results Both mGluR5 mRNA and protein were detected in the prenatal human hippocampus by real-time PCR and immunoblotting, and the expression levels increased gradually over time. The immunohistochemistry results were consistent with immunoblotting and showed that mGluR5 immunoreactivity was mainly present in the inner marginal zone （IMZ）, hippocampal plate （HP） and ventricular zone （VZ）. The double-labeling immunoftuorescence showed that mGluR5 was present in neural stem cells （nestin-positive）, neuroblasts （DCX-positive） and mature neurons （NeuN-positive）, but not in typical astrocytes （GFAP- positive）. The cells co-expressing mGluR5 and nestin were mainly located in the IMZ, HP and subplate at 11 weeks, all layers at 16 weeks, and CA 1 at 24 weeks. As development proceeded, the number of mGluR5/nestin double-positive cells decreased gradually so that there were only a handful of double-labeled cells at 32 weeks. However, mGluR5/DCX double-positive cells were only found in the HP, IZ and IMZ at 11 weeks. Conclusion The pattern ofmGluR5 expression by neural stern/progenitor cells, neuroblasts and neurons provides important anatomical evidence for the role of mGluR5 in the regulation of human hippocampal development.

Isoform-selective modulators for metabotropic glutamate receptors and protein kinase C:Synthesis and biological evaluation

The synthetic studies for some known modulators of metabotropic glutamate receptors (mGluRs) such as (S)-αM4CPG, (1S,3R)-ACPD, L-CCG-I are described. Based on the structure of αM4CPG several new conformationally constrained analogues are design ed and synthesized. Among them APICA is a selective antagonist for group II mGluRs. Also, a new benzolactam-V8 analogue is found to have better isoform-selectivity for protein kine C family. Three different protocols for synthesizing benzolactam-VS analogues are developed to meet the requirement for delivering more analogues to test.

c-Fos expression within the L_5 spinal cord dorsal horn after spinal nerve ligation in rats Is intraplantar administration of glutamate different from intrathecal administration?

BACKGROUND： Injection of glutamate （Glu） in normal animals can cause neuronal c-Fos expression; however, whether Glu can induce spinal neuronal c-Fos expression in pain models is unclear. OBJECTIVE： To examine the effects of intraplantar and intrathecal injection of Glu on c-Fos expression in the L5 spinal cord dorsal horn Ⅰ/Ⅱ and Ⅲ/Ⅳ layers after spinal nerve ligation, and to study the effects of the N-methyI-D-aspartic acid （NMDA） receptor antagonist, D-2-amino-5-phosphonopentanoate （D-AP5）, and a selective group I mGluR antagonist, 7-hydroyiminocyclo propan[a]chromen-lacarboxylic acid ethyl ester （cpccoEt）. DESIGN, TIME AND SETTING： A randomized, controlled animal study was performed at the Department of Pharmacology, Oral Anatomy, and Neurobiology, Osaka University Graduate School of Dentistry, from December 2005 to December 2006. MATERIALS： Glu （5 μmol）, D-AP5 （50 nmot） and cpccoEt （250 nmol） were provided by Wako Pure Chemical Industries, Osaka, Japan, and diluted in saline （50 μL）. The pH of all solutions was adjusted to 7.4. METHODS： Twelve rats were randomly divided into sham operation （n = 6） and spinal nerve ligation （SNL; n = 6） groups for behavioral assessments of neuropathic pain after ligation surgery of the left L5-6 nerve segment. Another 60 rats were randomly divided into sham operation, SNL, saline-intraplantar, saline-intrathecal, Glu-intraplantar, Glu-intrathecal, D-AP5-intrathecal, Glu-D-AP5-intrathecal, cpccoEt-intrathecal, and Glu-cpccoEt-intrathecal groups, with 6 rats in each group. All groups except sham operation group received a similar SNL. On day 14, rats received a 50-μL injection of saline, Glu, D-AP5, and/or cpccoEt into the left intraplantar or intrathecal L5-4 segments. MAIN OUTCOME MEASURES： The number of c-Fos positive neurons in both Ⅰ/Ⅱ and Ⅲ/Ⅳ spinal layers at L6 was observed using immunohistochemistry 2 hours after administration. RESULTS： （1） SNL increased the level of c-Fos expression in two sides of the spinal cord, particularly on Ⅲ/Ⅳ spinal layers of the ligated side. （2） Intraplantar or intrathecal administration of saline significantly increased the c-Fos labeled neurons in Ⅰ/Ⅱ spinal layers of the ligated side, compared with SNL alone （P 〈 0.01）. （3） Intraplantar Glu （5 μmol） increased the number of c-Fos positive neurons in Ⅰ/Ⅱ spinal layers compared with intraplantar saline （P〈 0.01）. （4） The number of c-Fos neurons in Ⅰ/Ⅱ spinal layers on both the ipsilateral and contralateral side after intraplantar Glu was lower than intrathecal Glu （P〈 0.01）, with a 3-fold higher induction by intrathecal Glu. （5） Co-administration of D-AP5 or cpccoEt reduced the effects of intrathecal Glu （P 〈 0.01）. CONCLUSION： Intrathecal Glu increases c-Fos expression more than intraplantar Glu. Antagonists of NMDA and group I mGluRs block this effect.

G-protein coupled receptors and synaptic plasticity in sleep deprivation

Insufficient sleep has been correlated to many physiological and psychoneurological disorders.Over the years,our understanding of the state of sleep has transcended from an inactive period of rest to a more active state involving important cellular and molecular processes.In addition,during sleep,electrophysiological changes also occur in pathways in specific regions of the mammalian central nervous system(CNS).Activity mediated synaptic plasticity in the CNS can lead to long-term and sometimes permanent strengthening and/or weakening synaptic strength affecting neuronal network behaviour.Memory consolidation and learning that take place during sleep cycles,can be affected by changes in synaptic plasticity during sleep disturbances.G-protein coupled receptors(GPCRs),with their versatile structural and functional attributes,can regulate synaptic plasticity in CNS and hence,may be potentially affected in sleep deprived conditions.In this review,we aim to discuss important functional changes that can take place in the CNS during sleep and sleep deprivation and how changes in GPCRs can lead to potential problems with therapeutics with pharmacological interventions.

Glutamate enhances the expression of vascular endothelial growth factor in cultured SD rat astrocytes

Objective To study the effect of glutamate on the expression of vascular endothelial growth factor (VEGF) mRNA and protein in cultured rat astrocytes. Methods Cultured rat astrocytes were randomly divided into 6 groups:control group (C),glutamate group (G),QA group (Q),DCG-IV group (D),L-AP4 group (L) and glutamate+MCPG group (G+M). Cells were cultured under nomoxic condition (95% air,5% CO2). RT-PCR and ELISA methods were used to detect the expression of VEGF mRNA and protein in cultured astrocytes,respectively. G+M group was preincubated with 1mM MCPG for 30 min prior to the stimulation with glutamate. There were 7 time points at 0,4,8,12,16,24 and 48 h in each group except G+M group. Results The expression of VEGF mRNA and protein did not differ significantly among D group,L group and C group. Different from that in C group,the expression of VEGF mRNA and protein could be enhanced both in a dose-dependent and time-dependent manner in G group and Q group. Meanwhile,the enhanced expression of VEGF mRNA and protein in G group was completely suppressed by MCPG after 24 h. Conclusion Glutamate can increase the expression of VEGF mRNA and protein in cultured astrocytes,which may be due to the activation of group I metabotropic glutamate receptors in astrocytes.

Do tau-synaptic long-term depression interactions in the hippocampus play a pivotal role in the progression of Alzheimer’s disease?

Cognitive decline in Alzheimer’s disease correlates with the extent of tau pathology,in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus.Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-βor long-term depression,a form of synaptic weakening involved in learning and memory,share similar mechanisms.Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging.Conversely,certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau,in particular,phosphorylation at residue Ser396.Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau(hyper)phosphorylation.We first summarize experimental evidence regarding tau-long-term depression interactions,followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer’s disease.Finally,we conclude with some thoughts and perspectives on future research about these interactions.

Mechanisms of glutamate metabolic function and dysfunction in vasculardementia

As the global population ages,research on the pathogenesis and treatment options for older patients with dementia has become increasingly important.Vascular dementia(VaD),the second most frequent type of dementia,is characterized by vascular impairment caused by inadequate blood supply to the brain.VaD is a complex neurological disorder involving multiple cells and signaling pathways,and its prevention and treatment pose clinical challenges with significant behavioral implications.Glutamate,the most abundant amino acid in the brain,plays a critical role as an excitatory neurotransmitter,impacting cognitive function,learning,and memory.Abnormal glutamate metabolism has been closely linked to dementia,and reduced blood flow to the brain can lead to excessive glutamate accumulation,resulting in neuronal death.This article highlights the connection between VaD and glutamate metabolism,aiming to identify better methods for preventing and treating VaD via regulating glutamate metabolism.

Why does a high-fat diet induce preeclampsia-like symptoms in pregnant rats?

Changes in neurotransmitter levels in the brain play an important role in epilepsy-like attacks after pregnancy-induced preeclampsia-eclampsia. Metabotropic glutamate receptor 1 participates in the onset of lipid metabolism disorder-induced preeclampsia. Pregnant rats were fed with a high-fat diet for 20 days. Thus, these pregnant rats experienced preeclampsia-like syndromes such as hyper-tension and proteinuria. Simultaneously, metabotropic glutamate receptor 1 mRNA and protein ex-pressions were upregulated in the rat hippocampus. These findings indicate that increased expres-sion of metabotropic glutamate receptor 1 promotes the occurrence of high-fat diet-induced pree-clampsia in pregnant rats.

Down-regulation of Homer1b/c expression protects cultured neurons after traumatic injury

Activation of metabotropic glutamate receptor la aggravates traumatic brain injury. The constitutively expressed protein Homerlb/c participates in delivering and anchoring metabotropic glutamate receptors in neurons. Here, we aimed to verify whether down-regulation of Homerlb/c by RNA interference could protect cultured rat cortical neurons from traumatic injury. We showed that 36 hours after transfection of Homerlb/c small interfering RNA, metabotropic glutamate receptor la was present only in the neuronal cytoplasm, but not in the dendrites. Calcium fluorescence intensity was also decreased significantly. Moreover, lactate dehydrogenase concentration was significantly decreased in Homerlb/c small interfering RNA-transfected cells compared with that in untransfected and control small interfering RNA-transfected cells 24 hours after traumatic neuronal injury. Our findings indicate that down-regulation of Homerlb/c could reduce metabotropic glutamate receptor la transfer from the cell body to the dendrite, relieve calcium overload, and protect neurons from traumatic injury.

Coexistence of Immune-Neuro-Endocrine Substances in the Rat Central Neurons

To investigate the expression of interleukin 2 (IL 2), metabotropic glutamate receptor subunit 1 (mGluR1) and estrogen receptor (ER) in neurons of the rat central nervous system (CNS) and identify the coexistence possibility of these immune neuro endocrine substances in the central neurons, the tri labeling immunocytochemical technique with different species specific primary antibodies (goat anti IL 2 antibody, rabbit anti mGluR1 antibody and mouse anti ER antibody ) were used to incubate two serial neighbor sections (one for demonstrating IL 2, another for mGluR1 and ER) of the cerebral cortex, medulla oblongata and spinal cord. There were IL 2 , mGluR1 and ER immunoreactivity (IR) positive labeled neurons in the above mentioned central areas. The IL 2 IR production showed brown color, located in the cytoplasm; In the neighbor serial section, the mGluR1 IR, production showed blue black color, located on the cell membrane; the ER IR production also showed brown color, located in the cytoplasm and nuclei. There were mGluR1/ER double labeled cells in the same section, which accounted for about 50 %-60 % of the total single and double labeled neurons. It was identified by projection check of serial neighbor sections that had mGluR1/ER/IL 2 tri labeled cells, which accounted for about 30 % of total mGluR1/ER double labeled neurons. The results indicate that mGluR1, ER and Il 2 can coexist in the same rat central neurons, therefore, providing morphological basis for the theory about immune neuro endocrine network at the cellular level for the first time.

EFFECTS OF NAAG AND MPEP ON RAT CORTICAL SPREADING DEPRESSION

Cortical spreading depression(CSD)is a pathophysiological phenomenon.There are sufficient evidences to prove that CSD plays an important role in some neurological disorders.However,exact mechanisms of its initiation and propagation are still unclear.Previous studies showed that glutamate receptors could be concerned with CSD,but those studies were mostly performed oriented to ionotropic glutamate receptors(iGluRs).There is relatively little report about effects of metabotropic glutamate receptors(mGluRs)on CSD.Here,we applied optical intrinsic signal imaging(OISI)combined with direct current(DC)potential recording to examine influences of some mGluRs antagonist(or agonist)on CSD propagation in rat’s brain,to indirectly validate actions of some mGluRs on CSD.We found that N-acetyl-l-aspartyl-l-glutamate(NAAG,an agonist at mGluR3)inhibited the propagation of CSD,and the inhibition was gradually developed with time.However,6-methyl-2-phenylethynyl-pyridine(MPEP,an antagonist of mGluR5)did not produce any significant alterations with the CSD propagation.Our findings suggest that mGluR3 could play an important role in the CSD propagation,but the activity of mGluR5 was comparatively weak.These findings can help to understand the propagation mechanism of CSD,and consider the therapy of some neurological diseases involved with CSD.

N-acetylaspartylglutamate Inhibits Heroin Self-Administration and Heroin-Seeking Behaviors Induced by Cue or Priming in Rats

Activation of presynaptic group II metabotropic glutamate receptors（mGluR2/3） inhibits drug reward and drug-seeking behavior, but the role of N-acetylaspartylglutamate（NAAG）, an agonist of endogenous mGluR2/3,in heroin reward and heroin-seeking behavior remained unclear. Here, we aimed to explore the effects of exogenous NAAG on heroin self-administration and heroinseeking behavior. First, rats were trained to self-administer heroin under a fixed ratio 1（FR1） schedule for 10 days,then received NAAG（50 or 100μg/10 μL in each nostril）in the absence or presence of LY341495（1 mg/kg, i.p.）, an antagonist of mGluR2/3, on day 11 and the effects of NAAG on heroin self-administration under FR1 were recorded for 3 consecutive days. Motivation was assessed in heroin self-administration under a progressive ratio schedule on day 11 in another 5 groups with the same doses of NAAG. Additional rats were withdrawn for 14 days after 14 days of heroin self-administration, then received the same pharmacological pretreatment and were tested for heroin-seeking behaviors induced by heroin priming or cues. The results showed that intranasal administration of NAAG significantly decreased intravenous heroin selfadministration on day 12, but not on day 11. Pretreatment with LY341495 prior to testing on day 12 prevented the inhibitory effect of NAAG on heroin reinforcement. The break-point for reward motivation was significantly reduced by NAAG. Moreover, NAAG also significantly inhibited the heroin-seeking behaviors induced by heroinpriming or cues and these were restored by pretreatment with LY341495. These results demonstrated that NAAG,via activation of presynaptic mGluR2/3, attenuated the heroin reinforcement, heroin motivational value, and heroin-seeking behavior, suggesting that it may be used as an adjunct treatment for heroin addiction.

New insights in the pathogenesis of alcohol-related liver disease:The metabolic,immunologic,and neurologic pathways

Alcohol-related liver disease(ALD)became an important health issue worldwide.Following chronic alcohol consumption,the development of ALD might be caused by metabolic and immunologic factors,such as reactive oxygen species(ROS)and pro-inflammatory cytokines.For example,hepatic cytochrome P4502E1 enzyme increases ROS production and stimulates de novo lipogenesis after alcohol exposure.In addition,damage-and pathogen-associated molecular patterns stimulate their specific receptors in nonparenchymal cells,including Kupffer cells,hepatic stellate cells(HSCs),and lymphocytes,which result in hepatocyte death and infiltration of pro-inflammatory cells(e.g.,neutrophils and macrophages)in the liver.Moreover,our studies have suggested the novel involvement of neurologic signaling pathways(e.g.,endocannabinoid and glutamate)through the metabolic synapse between hepatocytes and HSCs in the development of alcohol-related hepatic steatosis.Additionally,agouti-related protein and beta2-adrenergic receptors aggravate hepatic steatosis.Furthermore,organ-crosstalk has emerged as a critical issue in ALD.Chronic alcohol consumption induces dysbiosis and barrier disruption in the gut,leading to endotoxin leakage into the portal circulation,or lipolysis-mediated transport of triglycerides from the adipose tissue to the liver.In summary,this review addresses multiple pathogeneses of ALD,provides novel neurologic signaling pathways,and emphasizes the importance of organ-crosstalk in the development of ALD.