ASN NEURO最新文献

Summary statement: A_2A receptor required previous D₂ receptor activation to modulate Ca²⁺ currents. Istradefylline decreases pramipexole modulation on Ca²⁺ currents. Istradefylline reduces A_2A + neurons activity in striatial microcircuit, but pramipexole failed to further reduce neuronal activity.

Psychosine exerts most of its toxic effects by altering membrane dynamics with increased shedding of extracellular vesicles (EVs). In this study, we discovered that a fraction of psychosine produced in the brain of the Twitcher mouse, a model for Krabbe disease, is associated with secreted EVs. We evaluated the effects of attenuating EV secretion in the Twitcher brain by depleting ceramide production with an inhibitor of neutral sphingomyelinase 2, GW4869. Twitcher mice treated with GW4869 had decreased overall EV levels, reduced EV-associated psychosine and unexpectedly, correlated with increased disease severity. Notably, characterization of well-established, neuroanatomic hallmarks of disease pathology, such as demyelination and inflammatory gliosis, remained essentially unaltered in the brains of GW4869-treated Twitcher mice compared to vehicle-treated Twitcher controls. Further analysis of Twitcher brain pathophysiology is required to understand the mechanism behind early-onset disease severity in GW4869-treated mice. The results herein demonstrate that some pathogenic lipids like psychosine may be secreted using EV pathways. Our results highlight the relevance of this secretory mechanism as a possible contributor to spreading pathogenic lipids in neurological lipidoses.

Introduction: Febrile seizures (FS) are the most common neurological disease in childhood. The etiology of FS is the subject of numerous studies including studies regarding genetic predisposition. Aim: The aim of the study was to analyze the association of TRPV1 rs222747 and KCC2 rs2297201 gene polymorphisms with the occurrence of FS. Materials and Methods: The study included 112 patients diagnosed with FS classified as simple febrile seizures (SFS) or complex febrile seizures (CFS). We analyzed selected polymorphisms of KCC2 and TRPV1 genes using the Real-time PCR method. Results: The CT and TT genotypes of the rs2297201 polymorphism of the KCC2 gene are significantly more common in the group of children with FS than the control group (p = .002) as well as the allele T of this polymorphism (p = .045). Additionally, genotypes CT and TT of the rs2297201 polymorphism of the KCC2 gene were more frequent in the group of children with CFS compared to the control group (p < .001). Different genotypes and alleles of the rs222747 TRPV1 gene polymorphism were not associated with the occurrence of febrile seizures or epilepsy, nor were associated with the occurrence of a particular type of febrile seizure (p = .252). Conclusion: These results indicate that the CT and TT genotypes, as well as the T allele of rs2297201 polymorphism of the KCC2 gene, could be a predisposing factor for the FS, as well as the occurrence of CFS.

As the resident immune cells of the healthy nervous system, homeostatic microglia can rapidly become activated in response to injury/disease. Dysregulated microglia activation is a hallmark of nervous system disorders including neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. The elucidation of the biological and pathological roles of microglia has recently benefitted from the development of microglia-like cells using human induced pluripotent stem cell (iPSC)-based approaches. The success of iPSC-derived microglia preparations as a disease-relevant model system depends on their representation of the in vivo spatial and temporal heterogeneity of microglia under pathological conditions. Little is currently known about the potential of human iPSC-derived microglia generated using different methods for the study of neurodegenerative diseases. We compared the transcriptomes of human iPSC-derived microglia generated using two frequently used in vitro differentiation methods to determine whether separate strategies can generate microglia with distinct transcriptional signatures in vitro. We show that microglia derived using different differentiation methods display distinct maturation characteristics after equivalent times in culture. We also reveal that iPSC-derived microglia preparations generated using these two methods are composed of different subpopulations with transcriptomic signatures resembling those of in vivo regionally distinct microglia subtypes, specifically white-matter and gray-matter microglia. These findings highlight the need to better characterize the subtype composition of each microglia preparation prior to its use to model neurodegenerative diseases.

Oxytocin (OT), a nonapeptide, has a variety of functions. Despite extensive studies on OT over past decades, our understanding of its neural functions and their regulation remains incomplete. OT is mainly produced in OT neurons in the supraoptic nucleus (SON), paraventricular nucleus (PVN) and accessory nuclei between the SON and PVN. OT exerts neuromodulatory effects in the brain and spinal cord. While magnocellular OT neurons in the SON and PVN mainly innervate the pituitary and forebrain regions, and parvocellular OT neurons in the PVN innervate brainstem and spinal cord, the two sets of OT neurons have close interactions histologically and functionally. OT expression occurs at early life to promote mental and physical development, while its subsequent decrease in expression in later life stage accompanies aging and diseases. Adaptive changes in this OT system, however, take place under different conditions and upon the maturation of OT release machinery. OT can modulate social recognition and behaviors, learning and memory, emotion, reward, and other higher brain functions. OT also regulates eating and drinking, sleep and wakefulness, nociception and analgesia, sexual behavior, parturition, lactation and other instinctive behaviors. OT regulates the autonomic nervous system, and somatic and specialized senses. Notably, OT can have different modulatory effects on the same function under different conditions. Such divergence may derive from different neural connections, OT receptor gene dimorphism and methylation, and complex interactions with other hormones. In this review, brain functions of OT and their underlying neural mechanisms as well as the perspectives of their clinical usage are presented.

Summary statement: EAAT1/GLAST down-regulates its expression and function at the transcriptional level by activating a signaling pathway that includes PI3K, PKC and NF-κB, favoring the notion of an activity-dependent fine-tuning of glutamate recycling and its synaptic transactions through glial cells.

The circumventricular organs (CVOs) are unique areas within the central nervous system. They serve as a portal for the rest of the body and, as such, lack a blood-brain barrier. Microglia are the primary resident immune cells of the brain parenchyma. Within the CVOs, microglial cells find themselves continuously challenged and stimulated by local and systemic stimuli, even under steady-state conditions. Therefore, CVO microglia in their typical state often resemble the activated microglial forms found elsewhere in the brain as they are responding to pathological conditions or other stressors. In this review, I focus on the dynamics of CVO microglia, using the pineal gland as a specific CVO example. Data related to microglia heterogeneity in both homeostatic and unhealthy environments are presented and discussed, including those recently generated by using advanced single-cell and single-nucleus technology. Finally, perspectives in the CVO microglia field are also included.Summary StatementMicroglia in circumventricular organs (CVOs) continuously adapt to react differentially to the diverse challenges they face. Herein, I discuss microglia heterogeneity in CVOs, including pineal gland. Further studies are needed to better understand microglia dynamics in these unique brain areas. .

Neurotrophic herpes simplex virus type 1 (HSV-1) establishes lifelong latent infection in humans. Accumulating studies indicate that HSV-1, a risk factor of neurodegenerative diseases, exacerbates the sporadic Alzheimer's disease (AD). The analysis of viral genetic materials via genomic sequencing and quantitative PCR (qPCR) is the current approach used for the detection of HSV-1; however, this approach is limited because of its difficulty in detecting both latent and lytic phases of the HSV-1 life cycle in infected hosts. RNAscope, a novel in situ RNA hybridization assay, enables visualized detection of multiple RNA targets on tissue sections. Here, we developed a fluorescent multiplex RNAscope assay in combination with immunofluorescence to detect neuronal HSV-1 transcripts in various types of mouse brain samples and human brain tissues. Specifically, the RNA probes were designed to separately recognize two transcripts in the same brain section: (1) the HSV-1 latency-associated transcript (LAT) and (2) the lytic-associated transcript, the tegument protein gene of the unique long region 37 (UL37). As a result, both LAT and UL37 signals were detectable in neurons in the hippocampus and trigeminal ganglia (TG). The quantifications of HSV-1 transcripts in the TG and CNS neurons are correlated with the viral loads during lytic and latent infection. Collectively, the development of combinational detection of neuronal HSV-1 transcripts in mouse brains can serve as a valuable tool to visualize HSV-1 infection phases in various types of samples from AD patients and facilitate our understanding of the infectious origin of neurodegeneration and dementia.