Neuronal signaling最新文献

Alzheimer's disease (AD) is the leading cause of dementia affecting almost 50 million people worldwide. The ε4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor for late-onset AD cases, with homozygous APOE4 carriers being approximately 15-times more likely to develop the disease. With 25% of the population being APOE4 carriers, understanding the role of this allele in AD pathogenesis and pathophysiology is crucial. Though the exact mechanism by which ε4 allele increases the risk for AD is unknown, the processes mediated by APOE, including cholesterol transport, synapse formation, modulation of neurite outgrowth, synaptic plasticity, destabilization of microtubules, and β-amyloid clearance, suggest potential therapeutic targets. This review will summarize the impact of APOE on neurons and neuronal signaling, the interactions between APOE and AD pathology, and the association with memory decline. We will then describe current treatments targeting APOE4, complications associated with the current therapies, and suggestions for future areas of research and treatment.

CLN6-Batten disease is a rare neurodegenerative disorder with no cure, characterized by accumulation of lipofuscin in the lysosome, glial activation, and neuronal death. Here we test the therapeutic efficacy of modulating collapsin response mediator protein 2 (CRMP2) activity via S-N-benzy-2-acetamido-3-methoxypropionamide ((S)-Lacosamide) in a mouse model of CLN6-Batten disease. Promisingly, mouse neuronal cultures as well as Cln6 patient fibroblasts treated with varying concentrations of (S)-Lacosamide showed positive restoration of lysosomal associated deficits. However, while acute in vivo treatment enhanced glial activation in 3-month-old Cln6 mutant mice, chronic treatment over several months did not improve behavioral or long-term survival outcomes. Therefore, modulation of CRMP2 activity via (S)-Lacosamide alone is unlikely to be a viable therapeutic target for CLN6-Batten disease.

Neuroinflammation and neurogenesis have both been the subject of intensive investigation over the past 20 years. The sheer complexity of their regulation and their ubiquity in various states of health and disease have sometimes obscured the progress that has been made in unraveling their mechanisms and regulation. A recent study by Kozareva et al. (Neuronal Signaling (2019) 3), provides evidence that the orphan nuclear receptor TLX is central to communication between microglia and neural precursor cells and could help us understand how inflammation, mediated by microglia, influences the development of new neurons in the adult hippocampus. Here, we put recent studies on TLX into the context of what is known about adult neurogenesis and microglial activation in the brain, along with the many hints that these processes must be inter-related.

Primary neurons from rodent brain hippocampus and cortex have served as important tools in biomedical research over the years. However, protocols for the preparation of primary neurons vary, which often lead to conflicting results. This report provides a robust and reliable protocol for the production of primary neuronal cultures from the cortex and hippocampus with minimal contribution of non-neuronal cells. The neurons were grown in serum-free media and maintained for several weeks without any additional feeder cells. The neuronal cultures maintained according to this protocol differentiate and by 3 weeks develop extensive axonal and dendritic branching. The cultures produced by this method show excellent reproducibility and can be used for histological, molecular and biochemical methods.

Neuroblastoma (NB) is the most common extracranial solid tumor of early childhood; it accounts for approximately 8-10% of all childhood cancers and is the most common cancer in children in the first year of life. Patients in the high-risk group have a poor prognosis, with relapses being common and often refractory to drug treatment in those that survive. Moreover, the drug treatment itself can lead to a range of long-term sequelae. Therefore, there is a critical need to identify new therapeutics for NB. Isoliquiritigenin (ISLQ) is a naturally-occurring, dietary chalcone-type flavonoid with a range of biological effects that depend on the cell type and context. ISLQ has potential as an anticancer agent. Here we show that ISLQ has potent cytotoxic effects on SK-N-BE(2) and IMR-32 human NB cells, which carry amplification of the MYCN gene, the main prognostic marker of poor survival in NB. ISLQ was found to increase cellular reactive oxygen species (ROS). The cytotoxic effect of ISLQ was blocked by small molecule inhibitors of oxidative stress-induced cell death, and by the antioxidant N-acetyl-l-cysteine (NAC). Combined treatment of either SK-N-B-E(2) or IMR-32 cells with ISLQ and the anticancer agent cisplatin resulted in loss of cell viability that was greater than that induced by cisplatin alone. This study provides proof-of-principle that ISLQ is a potent cytotoxin for MYCN-amplified human NB cells. This is an important first step in rationalizing the further study of ISLQ as a potential adjunct therapy for high-risk NB.

Microglia are an essential component of the neurogenic niche in the adult hippocampus and are involved in the control of neural precursor cell (NPC) proliferation, differentiation and the survival and integration of newborn neurons in hippocampal circuitry. Microglial and neuronal cross-talk is mediated in part by the chemokine fractalkine/chemokine (C-X3-C motif) ligand 1 (CX3CL1) released from neurons, and its receptor CX3C chemokine receptor 1 (CX3CR1) which is expressed on microglia. A disruption in this pathway has been associated with impaired neurogenesis yet the specific molecular mechanisms by which this interaction occurs remain unclear. The orphan nuclear receptor TLX (Nr2e1; homologue of the Drosophila tailless gene) is a key regulator of hippocampal neurogenesis, and we have shown that in its absence microglia exhibit a pro-inflammatory activation phenotype. However, it is unclear whether a disturbance in CX3CL1/CX3CR1 communication mediates an impairment in TLX-related pathways which may have subsequent effects on neurogenesis. To this end, we assessed miRNA expression of up- and down-stream signalling molecules of TLX in the hippocampus of mice lacking CX3CR1. Our results demonstrate that a lack of CX3CR1 is associated with altered expression of TLX and its downstream targets in the hippocampus without significantly affecting upstream regulators of TLX. Thus, TLX may be a potential participant in neural stem cell (NSC)-microglial cross-talk and may be an important target in understanding inflammatory-associated impairments in neurogenesis.

Hemispheric lateralization is a fundamental organizing principle of nervous systems across taxonomic groups with bilateral symmetry. The mammalian hippocampus is lateralized anatomically, physiologically, and chemically; however, functional asymmetries are not yet well understood. Imaging studies in humans have implicated the left and right hippocampus in specialized processing. However, it is not clear if lateralized activity occurs in the rodent hippocampus. c-Fos imaging in animals provides a measure of neuronal activity with a resolution at the level of single cells. The aim of the present study was to determine whether lateralized activity-dependent c-Fos expression occurs in the rodent hippocampus. To understand functional lateralization of hippocampal processing, we compared interhemispheric expression of c-Fos in the dentate gyrus (DG), a structure involved in encoding new experiences, in mice that ran on a wheel, encoded a novel object, or remained in home cages. We found that wheel running (WR) induced the greatest amount of DG c-Fos expression in both hemispheres, with no difference between hemispheres. Object exploration (OB) resulted in left-lateralized DG c-Fos expression, whereas control (CON) mice were not lateralized. We then sought to determine whether differential consideration of hemispheres might influence the conclusions of a study by simulating common cell quantitation methods. We found that different approaches led to different conclusions. These data demonstrate lateralization of neuronal activity in the mouse DG corresponding to the experience of the animal and show that differentially considering hemisphere leads to alternative conclusions.

Cholinergic basal forebrain (cBF) neurons are defined by their expression of the p75 neurotrophin receptor (p75^NTR) and tropomyosin-related kinase (Trk) neurotrophin receptors in addition to cholinergic markers. It is known that the neurotrophins, particularly nerve growth factor (NGF), mediate cholinergic neuronal development and maintenance. However, the role of neurotrophin signalling in regulating adult cBF function is less clear, although in dementia, trophic signalling is reduced and p75^NTR mediates neurodegeneration of cBF neurons. Here we review the current understanding of how cBF neurons are regulated by neurotrophins which activate p75^NTR and TrkA, B or C to influence the critical role that these neurons play in normal cortical function, particularly higher order cognition. Specifically, we describe the current evidence that neurotrophins regulate the development of basal forebrain neurons and their role in maintaining and modifying mature basal forebrain synaptic and cortical microcircuit connectivity. Understanding the role neurotrophin signalling plays in regulating the precision of cholinergic connectivity will contribute to the understanding of normal cognitive processes and will likely provide additional ideas for designing improved therapies for the treatment of neurological disease in which cholinergic dysfunction has been demonstrated.

Background: Acute treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (Flx), induces anxiety-like behavioral effects. The serotonin_2A receptor (5-HT_2A) is implicated in the modulation of anxiety-like behavior, however its contribution to the anxiogenic effects of acute Flx remains unclear. Here, we examined the role of the 5-HT_2A receptor in the effects of acute Flx on anxiety-like behavior, serum corticosterone levels, neural activation and immediate early gene (IEG) expression in stress-responsive brain regions, using 5-HT_2A receptor knockout (5-HT_2A ^-/-) mice of both sexes. Methods: 5-HT_2A ^-/- and wild-type (WT) male and female mice received a single administration of Flx or vehicle, and were examined for anxiety-like behavior, serum corticosterone levels, FBJ murine osteosarcoma viral oncogene homolog peptide (c-Fos) positive cell numbers in stress-responsive brain regions of the hypothalamus and prefrontal cortex (PFC), and PFC IEG expression. Results: The increased anxiety-like behavior and enhanced corticosterone levels evoked by acute Flx were unaltered in 5-HT_2A ^-/- mice of both sexes. 5-HT_2A ^-/- female mice exhibited a diminished neural activation in the hypothalamus in response to acute Flx. Further, 5-HT_2A ^-/- male, but not female, mice displayed altered baseline expression of several IEGs (brain-derived neurotrophic factor (Bdnf), Egr2, Egr4, FBJ osteosarcoma gene (Fos), FBJ murine osteosarcoma viral oncogene homolog B (Fosb), Fos-like antigen 2 (Fosl2), Homer scaffolding protein (Homer) 1-3 (Homer1-3), Jun proto-oncogene (Jun)) in the PFC. Conclusion: Our results indicate that the increased anxiety and serum corticosterone levels evoked by acute Flx are not influenced by 5-HT_2A receptor deficiency. However, the loss of function of the 5-HT_2A receptor alters the degree of neural activation of the paraventricular nucleus (PVN) of the hypothalamus in response to acute Flx, and baseline expression of several IEGs in the PFC in a sexually dimorphic manner.

Mitochondria homeostasis is sustained by the mitochondrial quality control (MQC) system, which is crucial for cellular health, especially in the maintenance of functional mitochondria. A healthy mitochondria network is essential for life as it regulates cellular metabolism processes, particularly ATP production. Mitochondrial dynamics and mitophagy are two highly integrated processes in MQC system that determines whether damaged mitochondria will be repaired or degraded. Neurons are highly differentiated cells which demand high energy consumption. Therefore, compromised MQC processes and the accumulation of dysfunctional mitochondria may be the main cause of neuronal death and lead to neurodegeneration. Here, we focus on the inseparable relationship of mitochondria dynamics and mitophagy and how their dysfunction may lead to neurodegenerative diseases.