Cellular and Molecular Neurobiology最新文献

Tetrameric AMPA-type ionotropic glutamate receptors are primary transducers of fast excitatory synaptic transmission in the central nervous system, and their properties and abundance at the synaptic surface are crucial determinants of synaptic efficacy in neuronal communication across the brain. The induction of long-term potentiation (LTP) leads to the insertion of GluA1-containing AMPA receptors at the synaptic surface, whereas during long-term depression (LTD), these receptors are internalized into the cytoplasm of the spine. Disruptions in the trafficking of AMPA receptors to and from the synaptic surface attenuate both forms of synaptic plasticity. Homeostatic scaling up and scaling down, which are additional types of plasticity similar to LTP and LTD, are also regulated by the insertion and removal of GluA1-containing AMPA receptors from the synaptic surface. The trafficking of AMPA receptors is an intricate process assisted by various proteins. Furthermore, AMPA receptors are critical for the formation and consolidation of various types of memory, and alterations in their function are intimately associated with cognitive dysfunction in aging and several neurological and psychiatric diseases. In this review, we will provide an overview of the current understanding of how AMPA receptors regulate various forms of synaptic plasticity, their contribution to memory functions, and their role in aging and brain diseases.

Immune and metabolic factors play an important role in the onset and development of insomnia. This study aimed to investigate the causal relationship between insomnia and immune cells and metabolites. Data for 731 immune cell phenotypes, 1400 metabolites, and insomnia in this study were obtained from the GWAS open-access database. Two-way Mendelian randomization was used to (1) detect the causal relationship between immune cells and insomnia and (2) identify potential mediating metabolites. Mendelian randomization analysis identified eight immune cell phenotypes with a causal relationship to insomnia, and two immune cell phenotypes were protective factors for insomnia, namely CD8br %T cells and CD80 on CD62L + myeloid dendritic cells. The other six immune cell phenotypes were risk factors for insomnia, i.e., CD4/CD8br, CD16-CD56 on NKT, CCR2 on myeloid dendritic cells, CD40 on monocytes, CD38 on CD3-CD19-, and CD25 on CD45RA + CD4 not Treg. Further Mendelian randomization revealed 11 metabolites that were causally related to insomnia. Five metabolites were protective factors for insomnia, i.e., 3-hydroxy-3-methylglutarate, cholate, dodecanedioate, N-formylmethionine, and x-26054. Six metabolites were risk factors for insomnia, 3-amino-2-piperidone, 6-oxopiperdine-2-carboxylate, caffeine to theophylline ratio, leucine, maltose, and x-24736. In addition, our analysis showed that leucine mediated the association between CD4/CD8br and insomnia. From genetic information, we confirmed the causal relationship between insomnia, eight immune cell phenotypes, and eleven metabolite levels. Notably, we found a relationship between leucine-mediated CD4/CD8br and insomnia, providing evidence supporting the causal relationship between immune cell and insomnia, with plasma metabolites serving as mediators.

Both astroglia and microglia show region-specific distribution in CNS and often maladapt to age-associated alterations within their niche. Studies on autopsied substantia nigra (SN) of Parkinson's disease (PD) patients and experimental models propose gliosis as a trigger for neuronal loss. Epidemiological studies propose an ethnic bias in PD prevalence, since Caucasians are more susceptible than non-whites. Similarly, different mice strains are variably sensitive to MPTP. We had earlier likened divergent MPTP sensitivity of C57BL/6 J and CD-1 mice with differential susceptibility to PD, based on the numbers of SN neurons. We examined whether the variability was incumbent to inter-strain differences in glial features of male C57BL/6 J and CD-1 mice. Stereological counts showed relatively more microglia and fewer astrocytes in the SN of normal C57BL/6 J mice, suggesting persistence of an immune-vigilant state. MPTP-induced microgliosis and astrogliosis in both strains suggest their involvement in pathogenesis. ELISA of pro-inflammatory cytokines in the ventral-midbrain revealed augmentation of TNF-α and IL-6 at middle age in both strains that reduced at old age, suggesting middle age as a critical, inflamm-aging-associated time point. TNF-α levels were high in C57BL/6 J, through aging and post-MPTP, while IL-6 and IL-1β were upregulated at old age. CD-1 had higher levels of anti-inflammatory cytokine TGF-β. MPTP challenge caused upregulation of enzymes MAO-A, MAO-B, and iNOS in both strains. Post-MPTP enhancement in fractalkine and hemeoxygenase-1 may be neuron-associated compensatory signals. Ultrastructural observations of elongated astroglial/microglial mitochondria vis-à-vis the shrunken ones in neurons suggest a scale-up of their functions with neurotoxic consequences. Thus, astroglia and microglia may modulate aging and PD susceptibility.

In clinics, physical injuries to the spinal cord cause a temporary motor areflexia below lesion, known as spinal shock. This topic is still underexplored due to the lack of preclinical spinal cord injury (SCI) models that do not use anesthesia, which would affect spinal excitability. Our innovative design considered a custom-made micro impactor that provides localized and calibrated strikes to the ventral surface of the thoracic spinal cord of the entire CNS isolated from neonatal rats. Before and after injury, multiple ventral root (VR) recordings continuously traced respiratory rhythm, baseline spontaneous activities, and electrically induced reflex responses. As early as 200 ms after the lowering of the impactor, an immediate transient depolarization spread from the injury site to the whole spinal cord with distinct segmental velocities. Stronger strikes induced higher potentials causing, close by the site of injury, a transient drop in spinal cord oxygenation (SCO₂) and a massive cell death with a complete functional disconnection of input along the cord. Below the impact site, expiratory rhythm and spontaneous lumbar activity were suppressed. On lumbar VRs, reflex responses transiently halted but later recovered to control values, while electrically induced fictive locomotion remained perturbed. Moreover, low-ion modified Krebs solutions differently influenced impact-induced depolarizations, the magnitude of which amplified in low Cl^-. Overall, our novel ex vivo platform traces the immediate functional consequences of impacts to the spinal cord during development. This basic study provides insights on the SCI pathophysiology, unveiling an immediate chloride dysregulation.

It is difficult to distinguish Parkinson's disease (PD) in the early stage from those of various disorders including atypical Parkinson's syndrome (APS), vascular parkinsonism (VP), and even essential tremor (ET), because of the overlap of symptoms. Other, more challenging problems will arise when Parkinson's disease develops into Parkinson's disease dementia (PDD) in the middle and late stages. At this time, the differential diagnosis of PDD and DLB becomes thorny. These complicate the diagnostic process for PD, which traditionally heavily relies on symptomatic assessment and treatment response. Recent advances have identified several biomarkers in the blood and cerebrospinal fluid (CSF), including α-synuclein, lysosomal enzymes, fatty acid-binding proteins, and neurofilament light chain, whose concentration differs in PD and the related diseases. However, not all these molecules can effectively discriminate PD from related disorders. This review advocates for a paradigm shift toward biomarker-based diagnosis to effectively distinguish between PD and similar conditions. These biomarkers may reflect the diversity that exist among different diseases and provide an effective way to accurately understand their mechanisms. This review focused on blood and CSF biomarkers of PD that may have differential diagnostic value and the related molecular measurement methods with high diagnostic performance due to emerging technologies.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and memory deficit. Even with extensive research and studies, presently, there is no effective treatment for the management of AD. Besides, most of drugs used in the treatment of AD did not avert the AD neuropathology, and the disease still in a progressive status. For example, acetyl cholinesterase inhibitors are associated with many adverse effects, such as insomnia and nightmares. As well, acetylcholinesterase inhibitors augment cholinergic neurotransmission leading to the development of adverse effects related to high acetylcholine level, such as salivation, rhinorrhea, vomiting, loss of appetite, and seizure. Furthermore, tacrine has poor bioavailability and causes hepatotoxicity. These commonly used drugs do not manage the original causes of AD. For those reasons, natural products were repurposed for the treatment of AD and neurodegenerative diseases. It has been shown that phytochemicals produce neuroprotective effects against the development and progression of neurodegenerative diseases by different mechanisms, including antioxidant and anti-inflammatory effects. Quercetin (QCN) has been reported to exert an effective neuroprotective effect against AD and other neurodegenerative diseases by lessening oxidative stress. In this review, electronic databases such as PubMed, Scopus, and Web of Science were searched for possible relevant studies and article linking the effect of QCN on AD. Findings from this review highlighted that many studies highlighted different mechanistic signaling pathways regarding the neuroprotective effect of QCN in AD. Nevertheless, the precise molecular mechanism of QCN in AD was not completely clarified. Consequently, this review aims to discuss the molecular mechanism of QCN in AD.