Neuronal Signal Transduction Pathways Research Articles

Navigating the Fractional Calcium Dynamics of Orai Mechanism in Polar Dimensions.

Calcium plays a crucial role as a second messenger in neuronal signal transduction pathways. The influx of calcium ions through various physicochemical gating channels activates neuronal calcium signaling. The Endoplasmic Reticulum (ER) is a significant intracellular structure that sequesters calcium and controls signaling through SERCA, IPR, and leak channel mechanisms. Disruption of calcium dynamics can trigger intrinsic dyshomeostasis, cell damage, and apoptosis. The present study articulates a Caputo fractional time derivative in the polar coordinate dimensions to investigate the role of nonlocal calcium-free ions in the neuron through the Orai channel, and ER fluxes, incorporating various physiological parameters. The solution was obtained through the hybrid integral transform technique for analytical form. The closed form was generated using Green's function in terms of Mainardi and Wright's functions. Our simulation uncovered the calcium concentration bandwidth of interaction with different neuronal parameters. Parameters and calcium ion synergy show normal and Alzheimer's disease-impacted interaction through different illustrations. Our simulation reveals that S100B and BAPTA have significant calcium-controlling behavior.

Exploring hub genes and crucial pathways linked to oxidative stress in bipolar disorder depressive episodes through bioinformatics analysis.

Bipolar disorder (BD) is a complex and serious psychiatric condition primarily characterized by bipolar depression, with the underlying genetic determinants yet to be elucidated. There is a substantial body of literature linking psychiatric disorders, including BD, to oxidative stress (OS). Consequently, this study aims to assess the relationship between BD and OS by identifying key hub genes implicated in OS pathways. We acquired gene microarray data from GSE5392 through the Gene Expression Omnibus (GEO). Our approach encompassed differential expression analysis, weighted gene co-expression network analysis (WGCNA), and Protein-Protein Interaction (PPI) Network analysis to pinpoint hub genes associated with BD. Subsequently, we utilized Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) to identify hub genes relevant to OS. To evaluate the diagnostic accuracy of these hub genes, we performed receiver operating characteristic curve (ROC) analysis on both GSE5388 and GSE5389 datasets. Furthermore, we conducted a study involving ten BD patients and ten healthy controls (HCs) who met the special criteria, assessing the expression levels of these hub genes in their peripheral blood mononuclear cells (PBMCs). We identified 411 down-regulated genes and 69 up-regulated genes for further scrutiny. Through WGCNA, we obtained 22 co-expression modules, with the sienna3 module displaying the strongest association with BD. By integrating differential analysis with genes linked to OS, we identified 44 common genes. Subsequent PPI Network and WGCNA analyses confirmed three hub genes as potential biomarkers for BD. Functional enrichment pathway analysis revealed their involvement in neuronal signal transduction, oxidative phosphorylation, and metabolic obstacle pathways. Using the Cytoscape plugin "ClueGo assay," we determined that a majority of these targets regulate neuronal synaptic plasticity. ROC curve analysis underscored the excellent diagnostic value of these three hub genes. Quantitative reverse transcription-PCR (RT-qPCR) results indicated significant changes in the expression of these hub genes in the PBMCs of BD patients compared to HCs. We identified three hub genes (TAC1, MAP2K1, and MAP2K4) in BD associated with OS, potentially influencing the diagnosis and treatment of BD. Based on the GEO database, our study provides novel insights into the relationship between BD and OS, offering promising therapeutic targets.

Mice with exonic RELN deletion identified from a patient with schizophrenia have impaired visual discrimination learning and reversal learning in touchscreen operant tasks

The Reelin gene (RELN) encodes a large extracellular protein, which has multiple roles in brain development and adult brain function. It activates a series of neuronal signal transduction pathways in the adult brain that function in synaptic plasticity, dendritic morphology, and cognitive function. To further investigate the roles of Reln in brain function, we generated a mouse line using the C57BL/6 J strain with the specific Reln deletion identified from a Japanese patient with schizophrenia (Reln-del mice). These mice exhibited abnormal sociality, but the pathophysiological significance of the Reln deletion for higher brain functions, such as learning and behavioral flexibility remains unclear. In this study, cognitive function in Reln-del mice was assessed using touchscreen-based visual discrimination (VD) and reversal learning (RL) tasks. Reln-del mice showed normal learning in the simple VD task, but the learning was delayed in the complex VD task as compared to their wild-type (WT) littermates. In the RL task, sessions were divided into early perseverative phase (sessions with <50% correct) and later learning phase (sessions with ≥50% correct). Reln-del mice showed normal perseveration but impaired relearning ability in both simple RL and complex RL task as compared to WT mice. These results suggest that Reln-del mice have impaired learning ability, but the behavioral flexibility is unaffected. Overall, the observed behavioral abnormalities in Reln-del mice suggest that this mouse model is a useful preclinical tool for investigating the neurobiological mechanism underlying cognitive impairments in schizophrenia and a therapeutic strategy.

Extracellular Metalloproteinases in the Plasticity of Excitatory and Inhibitory Synapses.

Long-term synaptic plasticity is shaped by the controlled reorganization of the synaptic proteome. A key component of this process is local proteolysis performed by the family of extracellular matrix metalloproteinases (MMPs). In recent years, considerable progress was achieved in identifying extracellular proteases involved in neuroplasticity phenomena and their protein substrates. Perisynaptic metalloproteinases regulate plastic changes at synapses through the processing of extracellular and membrane proteins. MMP9 was found to play a crucial role in excitatory synapses by controlling the NMDA-dependent LTP component. In addition, MMP3 regulates the L-type calcium channel-dependent form of LTP as well as the plasticity of neuronal excitability. Both MMP9 and MMP3 were implicated in memory and learning. Moreover, altered expression or mutations of different MMPs are associated with learning deficits and psychiatric disorders, including schizophrenia, addiction, or stress response. Contrary to excitatory drive, the investigation into the role of extracellular proteolysis in inhibitory synapses is only just beginning. Herein, we review the principal mechanisms of MMP involvement in the plasticity of excitatory transmission and the recently discovered role of proteolysis in inhibitory synapses. We discuss how different matrix metalloproteinases shape dynamics and turnover of synaptic adhesome and signal transduction pathways in neurons. Finally, we discuss future challenges in exploring synapse- and plasticity-specific functions of different metalloproteinases.

Intracranial self-stimulation-reward or immobilization-aversion had different effects on neurite extension and the ERK pathway in neurotransmitter-sensitive mutant PC12 cells

Various actions trigger pleasure (reward) or aversion (punishment) as emotional responses. Emotional factors that negatively affect brain neural control processes for long periods of time might cause various mental diseases by inducing neuronal changes. In the present study, newly developed PC12m12 cells which are highly sensitivity to neurotransmitters such as acetylcholine (ACh), were used. Exposing the cells to plasma from rats that had been subjected to intracranial self-stimulation (ICSS) markedly upregulated neurite outgrowth. In addition, voluntary running in a wheel or forced on a rotating rod was used to induce behavioral excitation in rats, and examinations of their plasma confirmed that the ICSS-induced neurite outgrowth was not associated with the ICSS behavior itself. Furthermore, immunoblotting and treatment with U0126, an ERK (extracellular signal-regulated kinase) antagonist, showed that the ICSS-induced neurite outgrowth was related to neuronal ERK activity. Exposing the same cells to plasma from rats that had been subjected to immobilization (IMM) also increased neurite outgrowth. Although the degree of enhancement was not as great as that seen after the ICSS rat plasma treatment, it was less than that observed after treatment with ACh as a positive control. These results indicate that ICSS or IMM lead to varying degrees of morphological changes, such as enhanced neurite outgrowth, in PC12m12 cells, but the neuronal signal transduction pathways underlying these effects differ; i.e.,the former morphological change might involve the activation of the ERK pathway, whereas the latter changes might not. Using PC12m12 cells which exhibit sensitivity to neurotransmitters, it might be possible to clarify the pathogeneses of mental diseases at the neuronal level and search for therapeutic drugs.

Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions

Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). However, how Slitrks participate in activation of intracellular signaling pathways in postsynaptic neurons remains largely unknown. Here we report that, among the six members of the Slitrk family, only Slitrk2 directly interacts with the PDZ domain-containing excitatory scaffolds, PSD-95 and Shank3. The interaction of Slitrk2 with PDZ proteins is mediated by the cytoplasmic COOH-terminal PDZ domain-binding motif (Ile-Ser-Glu-Leu), which is not found in other Slitrks. Mapping analyses further revealed that a single PDZ domain of Shank3 is responsible for binding to Slitrk2. Slitrk2 forms in vivo complexes with membrane-associated guanylate kinase (MAGUK) family proteins in addition to PSD-95 and Shank3. Intriguingly, in addition to its role in synaptic targeting in cultured hippocampal neurons, the PDZ domain-binding motif of Slitrk2 is required for Slitrk2 promotion of excitatory synapse formation, transmission, and spine development in the CA1 hippocampal region. Collectively, our data suggest a new molecular mechanism for conferring isoform-specific regulatory actions of the Slitrk family in orchestrating intracellular signal transduction pathways in postsynaptic neurons.

1789-P: Ser/Thr Phosphatase-PP2C Negatively Regulates AS160 and GSK3β Activity in Neuronal Insulin Signal Transduction Pathway

Serine/Threonine protein phosphatases regulate the activity of insulin signaling molecules involved in glucose homeostasis. Aberration in their functions have been reported in adipocytes, hepatocytes and skeletal muscle cells lead to abnormalities in signal transduction causing diabetes. Neuronal system is insulin responsive. Malfunctions have been reported to lead to development of metabolic disorders like diabetic neuropathy and Alzheimer disease. Our understanding of phosphatase mediated regulation in general is anyway very limited and role of PP2C in insulin signaling pathway in neuronal system is practically non-existent. Further exploration is required to understand the role of Ser/Thr phosphatases in neuronal system. Therefore, the aim of this work was to identify the role of PP2C in neuronal insulin signaling. To achieve this, PP2C in the differentiated Neuro-2a (N2A) cells was inhibited by treating with a potent and specific inhibitor of PP2C, Sanguinarine Chloride (SC), in presence (100nM) or absence of insulin and the effect was tested on the activity of AS160 and GSK3β. In insulin stimulated state inhibition of PP2C caused a significant 37% and 56% of decrease in the phosphorylation of AS160 at Ser588 and Thr642 residues, respectively. Similarly, a 37% decrease was observed in phosphorylation of GSK3β at Ser9. However, the expression of AS160 and GSK3β were found to be unaffected. Data shows for the first time that PP2C mediated dephosphorylation might be involved in regulating the activity of AS160 and GSK3β in neuronal system and hence suggest a possibility of its playing a major negative role in regulating neuronal insulin signal transduction pathway. Disclosure Y. Yadav: None. C.S. Dey: None. Funding Department of Science &amp; Technology, Government of India, New Delhi; Department of Science &amp; Technology, Government of India, New Delhi (SR/S2/JCB-24/2008(G))

Diabetes and Alzheimer's Disease: Can Tea Phytochemicals Play a Role in Prevention?

Dementia and diabetes mellitus are prevalent disorders in the elderly population. While recognized as two distinct diseases, diabetes has more recently recognized as a significant contributor to risk for developing dementia, and some studies make reference to type 3 diabetes, a condition resulting from insulin resistance in the brain. Alzheimer's disease, the most common form of dementia, and diabetes, interestingly, share underlying pathological processes, commonality in risk factors, and, importantly, pathways for intervention. Tea has been suggested to possess potent antioxidant properties. It is rich in phytochemicals including, flavonoids, tannins, caffeine, polyphenols, boheic acid, theophylline, theobromine, anthocyanins, gallic acid, and finally epigallocatechin-3-gallate, which is considered to be the most potent active ingredient. Flavonoid phytochemicals, known as catechins, within tea offer potential benefits for reducing the risk of diabetes and Alzheimer's disease by targeting common risk factors, including obesity, hyperlipidemia, hypertension, cardiovascular disease, and stroke. Studies also show that catechins may prevent the formation of amyloid-β plaques and enhance cognitive functions, and thus may be useful in treating patients who have Alzheimer's disease or dementia. Furthermore, other phytochemicals found within tea offer important antioxidant properties along with innate properties capable of modulating intracellular neuronal signal transduction pathways and mitochondrial function.

ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion

Human apolipoprotein E (ApoE) apolipoprotein is primarily expressed in three isoforms (ApoE2, ApoE3, and ApoE4) that differ only by two residues. ApoE4 constitutes the most important genetic risk factor for Alzheimer's disease (AD), ApoE3 is neutral, and ApoE2 is protective. How ApoE isoforms influence AD pathogenesis, however, remains unclear. Using ES-cell-derived human neurons, we show that ApoE secreted by glia stimulates neuronal Aβ production with an ApoE4> ApoE3> ApoE2 potency rank order. We demonstrate that ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases. Activated ERK1/2 induces cFos phosphorylation, stimulating the transcription factor AP-1, which in turn enhances transcription of amyloid-β precursor protein (APP) and thereby increases amyloid-β levels. This molecular mechanism also regulates APP transcription in mice invivo. Our data describe a novel signal transduction pathway in neurons whereby ApoE activates a non-canonical MAP kinase cascade that enhances APP transcription and amyloid-β synthesis.

Potassium Channels and Signal Transduction Pathways in Neurons

Potassium (K+) channels constitute the most diverse class of ion channels; these channels are especially important for regulation of the neuronal excitability and provide signaling activity in a variety of ways. These channels are major determinants of the membrane excitability, influencing the resting potential of the membranes, waveforms and frequencies of action potentials, and thresholds of excitation. Voltagegated K+ channels do not exist as independent units merely responding to changes in the transmembrane potential; these are macromolecular complexes able to integrate a great variety of cellular signals that provide fine tuning of channel activities. Compounds that change K+ channel properties are commonly employed as therapeutic agents in a number of pathologies, in particular arrhythmias, cancer, and neurological disorders (psychoses, epilepsy, stroke, and Alzheimer’s disease).

Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation.

Exosomes are small membranous vesicles of endocytic origin that are released by almost every cell type. They exert versatile functions in intercellular communication important for many physiological and pathological processes. Recently, exosomes attracted interest with regard to their role in cell-cell communication in the nervous system. We have shown that exosomes released from oligodendrocytes upon stimulation with the neurotransmitter glutamate are internalized by neurons and enhance the neuronal stress tolerance. Here, we demonstrate that oligodendroglial exosomes also promote neuronal survival during oxygen-glucose deprivation, a model of cerebral ischaemia. We show the transfer from oligodendrocytes to neurons of superoxide dismutase and catalase, enzymes which are known to help cells to resist oxidative stress. Additionally, we identify various effects of oligodendroglial exosomes on neuronal physiology. Electrophysiological analysis using in vitro multi-electrode arrays revealed an increased firing rate of neurons exposed to oligodendroglial exosomes. Moreover, gene expression analysis and phosphorylation arrays uncovered differentially expressed genes and altered signal transduction pathways in neurons after exosome treatment. Our study thus provides new insight into the broad spectrum of action of oligodendroglial exosomes and their effects on neuronal physiology. The exchange of extracellular vesicles between neural cells may exhibit remarkable potential to impact brain performance.

Effect of ginsenoside Rb1 on insulin signal transduction pathway in hippocampal neurons of high-glucose-fed rats

To study the effect of ginsenoside Rb1 on GSKbeta/IDE signal transduction pathway and Abeta protein secretion in hippocampal neurons of high glucose-treated rats. Hippocampal neurons of 24 h-old newly born SD rats were primarily cultured, inoculated in culture medium under different conditions, and then divided into the normal group, the high glucose group, the LiCl group and the Rb1 group. After being cultured for 72 h, the expressions of their phosphorylated GSK3beta, total GSK3beta and IDE protein were detected by Western blotting analysis. The mRNA expressions of GSK3beta and IDE were determined by RT-PCR. The ELISA assay was used to detect the secretion of Abeta protein in cell supernatant. Compared with the normal group, the high glucose group showed increase in the p/tGSK3beta protein ratio and the secretion of Abeta protein and decrease in IDE protein and mRNA (P < 0.05). Compared with the high glucose group, both Rb1 and LiCl groups showed decrease in the p/tGSK3beta protein ratio and the expression of Abeta protein and increase in IDE protein and mRNA expression (P < 0.05). Compared with the LiCl group, the Rb1 group showed no significant difference in the expressions of p/tGSK3beta protein, IDE protein, mRNA and Abeta protein expression. In addition, the GSK3beta mRNA expression of the four groups had no significant difference. Ginsenoside Rb1 may reduce the secretion of Abeta protein in hippocampal neurons by reducing the phosphorylation of GSK3beta, down-regulating the ratio of pGSK3beta/GSK3beta and upregulating the expression of IDE.

Sex‐related differences in death control of somatic cells

Sex‐related differences in death control of somatic cells

Roles of Phosphotase 2A in Nociceptive Signal Processing

Multiple protein kinases affect the responses of dorsal horn neurons through phosphorylation of synaptic receptors and proteins involved in intracellular signal transduction pathways, and the consequences of this modulation may be spinal central sensitization. In contrast, the phosphatases catalyze an opposing reaction of de-phosphorylation, which may also modulate the functions of crucial proteins in signaling nociception. This is an important mechanism in the regulation of intracellular signal transduction pathways in nociceptive neurons. Accumulated evidence has shown that phosphatase 2A (PP2A), a serine/threonine specific phosphatase, is implicated in synaptic plasticity of the central nervous system and central sensitization of nociception. Therefore, targeting protein phosphotase 2A may provide an effective and novel strategy for the treatment of clinical pain. This review will characterize the structure and functional regulation of neuronal PP2A and bring together recent advances on the modulation of PP2A in targeted downstream substrates and relevant multiple nociceptive signaling molecules.

Exploring the dominant role of Cav1 channels in signalling to the nucleus

Calcium is important in controlling nuclear gene expression through the activation of multiple signal-transduction pathways in neurons. Compared with other voltage-gated calcium channels, CaV1 channels demonstrate a considerable advantage in signalling to the nucleus. In this review, we summarize the recent progress in elucidating the mechanisms involved. CaV1 channels, already advantaged in their responsiveness to depolarization, trigger communication with the nucleus by attracting colocalized clusters of activated CaMKII (Ca2+/calmodulin-dependent protein kinase II). CaV2 channels lack this ability, but must work at a distance of >1 μm from the CaV1-CaMKII co-clusters, which hampers their relative efficiency for a given rise in bulk [Ca2+]i (intracellular [Ca2+]). Moreover, Ca2+ influx from CaV2 channels is preferentially buffered by the ER (endoplasmic reticulum) and mitochondria, further attenuating their effectiveness in signalling to the nucleus.

A Model of the Intracellular Response of an Olfactory Neuron in Caenorhabditis elegans to Odor Stimulation

We developed a mathematical model of a hypothetical neuronal signal transduction pathway to better understand olfactory perception in Caenorhabditis elegans. This worm has only three pairs of olfactory receptor neurons. Intracellular Ca2+ decreases in one pair of olfactory neurons in C. elegans, the AWC neurons, following application of an attractive odor and there is a transient increase in intracellular Ca2+ following removal of odor. The magnitude of this increase is positively correlated with the duration of odor stimulation. Additionally, this Ca2+ transient is induced by a cGMP second messenger system. We identified likely candidates for the signal transduction molecules functioning in this system based on available gene expression and physiological data from AWCs. Our model incorporated a G-protein-coupled odor receptor, a G-protein, a guanylate cyclase as the G-protein effector, and a single phosphodiesterase. Additionally, a cyclic-nucleotide-gated ion channel and a voltage-gated ion channel that mediated calcium influx were incorporated into the model. We posited that, upon odor stimulation, guanylate cyclase was suppressed by the G-protein and that, upon cessation of the stimulus, the G-protein–induced suppression ceased and cGMP synthesis was restored. A key element of our model was a Ca2+-dependent negative feedback loop that ensured that the calcium increases were transient. Two guanylate cyclase-activating proteins acted on the effector guanylate cyclase to negatively regulate cGMP signaling and the resulting calcium influx. Our model was able to closely replicate in silico three important features of the calcium dynamics of AWCs. Specifically, in our simulations, [Ca2+] increased rapidly and reached its peak within 10 s after the odor stimulus was removed, peak [Ca2+] increased with longer odor exposure, and [Ca2+] decreased during a second stimulus that closely followed an initial stimulus. However, application of random background signal (‘noise’) showed that certain components of the pathway were particularly sensitive to this noise.

Effect of heme oxygenase-1 on CDK5-ATM-P53 signal transduction pathway in rat hippocampal neurons subjected to oxygen-glucose deprivation injury

Objective To investigate the effect of heme oxygenase-1 (HO-1) on cyclin-dependent kinase 5 (CDK5)-ataxia telangiectasia mutated (ATM)-P53 signal transduction pathway in rat hippocampal neurons subjected to oxygen-glucose deprivation (OGD) injury.Methods Hippocampal neurons of newborn Wistar rats ( ＜ 48 h) were cultured for 7 days in vitro.The primary cultured neurons were randomly divided into 4 groups with 10 wells in each group:control group (group C),OGD (group D),OGD + hemin (HO-1 inducer) group (group D + H ) and OGD + hemin + zinc protoporphyrin ( HO-1 inhibitor) group ( group D + H + T).For OGD experiments,cultures were washed three times in a glucose-free balanced salt solution (BSS).They were then placed in deoxygenated glucose-free medium and sealed under 95％ N2-5％ CO2 in an anaerobic chamber equilibrated to 37°C and 100％ humidity for 45 min.OGD was terminated by replacement of stored medium and by returning the cultures to a standard incubator maintained at 37 ℃ in 95％ air-5％ CO2.The OGD model was established after the neurons were preconditioned with hemin 10 μmol/L for 24 h in group D + H.The OGD model was established after the neurons were preconditioned with hemin 10 μmol/L and zinc protoporphyrin 10 μmol/L for 24 h in group D + H + T.After 24 h of culture,the neuronal viability,apoptosis rate,and expression of HO-1 mRNA and protein,and CDK5,ATM and P53 protein were detected.Results Compared with group C,the expression of HO-1 mRNA,and HO-1,CDK5,ATM and P53 protein was up-regulated,the neuronal viability was significantly decreased,and the apoptosis rate was significantly increased in group D (P ＜ 0.01 ).Compared with group D,the expression of HO-1 mRNA and protein was up-regulated,the expression of CDK5,ATM and P53 protein was down-regulated,the neuronal viability was significantly increased,and the apoptosis rate was significanlly decreased in group D + H ( P ＜ 0.01 ).Compared with group D + H,the expression of HO-1 mRNA and protein was down-regulated,the expression of CDK5,ATM and P53 protein was up-regulated,the neuronal viability was significantly decreased,and the apoptosis rate was significantly increased in group D + H + T ( P ＜ 0.01 ).Conclusion HO-1 can inhibit neuronal apoptosis through blocking CDK5-ATM-P53 signal transduction pathway in rat hippocampal neurons subjected to OGD injury. Key words: Heme oxygenase-1; Anoxia; Hippocampus; Neurons; Cyclin-dependent kinase 5; Ataxia telangiectasia; Genes; Genes,p53

Altered calcium signaling following traumatic brain injury.

Cell death and dysfunction after traumatic brain injury (TBI) is caused by a primary phase, related to direct mechanical disruption of the brain, and a secondary phase which consists of delayed events initiated at the time of the physical insult. Arguably, the calcium ion contributes greatly to the delayed cell damage and death after TBI. A large, sustained influx of calcium into cells can initiate cell death signaling cascades, through activation of several degradative enzymes, such as proteases and endonucleases. However, a sustained level of intracellular free calcium is not necessarily lethal, but the specific route of calcium entry may couple calcium directly to cell death pathways. Other sources of calcium, such as intracellular calcium stores, can also contribute to cell damage. In addition, calcium-mediated signal transduction pathways in neurons may be perturbed following injury. These latter types of alterations may contribute to abnormal physiology in neurons that do not necessarily die after a traumatic episode. This review provides an overview of experimental evidence that has led to our current understanding of the role of calcium signaling in death and dysfunction following TBI.

Neuronal signaling and behavior

Neuronal signaling and behavior

Role of activating transcription factor 3 in ischemic penumbra region following transient middle cerebral artery occlusion and reperfusion injury

The activating transcription factor 3 (ATF3) is expressed by various types of cellular insults. It has been suggested to serve diverse functions in both cellular survival and death signal cascades, but the exact role of ATF3 in brain ischemia is little known so far. Thus, the authors examined the expression pattern of ATF3 following middle cerebral artery occlusion (MCAO) and reperfusion injury. At 1–2 days after MCAO and reperfusion injury, numerous number of ATF3-immunoreacitive (-ir) nuclei was observed in the ipsilateral peri-infarct cortex, but declined rapidly at 3 days. Almost all ATF3-ir nuclei were co-localized with NeuN-ir neurons. Neither GFAP- nor OX42-ir neuroglia were co-localized with ATF3. Double labeling of Fluoro-Jade B with ATF3 showed that ATF3-ir nuclei mismatched with Fluoro-Jade B-ir neurons. To further examine the role of ATF3 in ischemic peri-infarct regions, double immunofluorescent labeling of ATF3/caspase 3, ATF3/Bcl-xl, and ATF3/HSP27 was conducted. Semiquantitive estimation showed that about 15% of ATF3-ir neurons also expressed caspase 3. However, about only 0.4% and 2.6% of ATF3-ir neurons were double-stained with Bcl-xl and Hsp27, respectively. Consequently, it would be suggested that ATF3 seem to play an important role in caspase-dependent neuronal apoptotic signal transduction pathways caused by focal cerebral ischemia and reperfusion injury.