Frontiers in Cellular Neuroscience最新文献

Ferroptosis represents an iron^- and lipid peroxidation (LPO)-mediated form of regulated cell death (RCD). Recent evidence strongly suggests the involvement of ferroptosis in various neurodegenerative diseases (NDs), particularly Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), among others. The treatment of ferroptosis poses both opportunities and challenges in the context of ND. This review provides a comprehensive overview of characteristic features, induction and inhibition of ferroptosis, highlighting the ferroptosis inhibitor and the underlying mechanisms responsible for its occurrence. Moreover, the review explores how these mechanisms contribute to the pathogenesis and progression of major neurodegenerative disorders. Additionally, it presents novel insights into the role of ferroptosis in ND and summarizes recent advancements in the development of therapeutic approaches targeting ferroptosis. These insights and advancements hold potential to guide future strategies aimed at effectively managing these debilitating medical conditions.

Deoxyhypusine synthase (DHPS) catalyzes the initial step of hypusine incorporation into the eukaryotic initiation factor 5A (eIF5A), leading to its activation. The activated eIF5A, in turn, plays a key role in regulating the protein translation of selected mRNAs and therefore appears to be a suitable target for therapeutic intervention strategies. In the present study, we analyzed the role of DHPS-mediated hypusination in regulating neuronal homeostasis using lentivirus-based gain and loss of function experiments in primary cortical cultures from rats. This model allows us to examine the impact of DHPS function on the composition of the dendritic and synaptic compartments, which may contribute to a better understanding of cognitive function and neurodevelopment in vivo. Our findings revealed that shRNA-mediated DHPS knockdown diminishes the amount of hypusinated eIF5A (eIF5A^Hyp), resulting in notable alterations in neuronal dendritic architecture. Furthermore, in neurons, the synaptic composition was also affected, showing both pre- and post-synaptic changes, while the overexpression of DHPS had only a minor impact. Therefore, we hypothesize that interfering with the eIF5A hypusination caused by reduced DHPS activity impairs neuronal and synaptic homeostasis.

Human voltage-gated potassium (Kv) channels are expressed by a 40-member gene family that is essential for normal electrical activity and is closely linked to various excitability disorders. Function-altering sequence variants in the KCNB1 gene, which encodes the neuronally expressed Kv2.1 channel, are associated with neurodevelopmental disorders including developmental delay with or without epileptic activity. In this study, we describe a 40-month-old fraternal twin who presented with severe neurodevelopmental delay. Electroencephalogram recordings at 19 months of age revealed poor sleep architecture and the presence of multifocal epileptiform discharges. The individual's fraternal twin was neurotypical, and there was no family history of neurodevelopmental delay or seizures. Whole genome sequencing at 33 months of age for the proband revealed a de novo variant in KCNB1 [c.1154C > T/p.Pro385Leu], encoding a proline-to-leucine substitution at residue 385, in the extracellular region immediately preceding Kv2.1 transmembrane segment 6 (S6). Cellular electrophysiological analysis of the effects of the gene variant in heterologously expressed Kv2.1 demonstrated that homozygous Kv2.1-P385L channels were completely non-functional. Channels generated by a 50/50 expression of wild-type Kv2.1 and Kv2.1-P385L, designed to mimic the proband's heterozygous status, revealed a partially dominant-negative effect, resulting in an 81% reduction in current magnitude. The dramatic loss of function in Kv2.1 is the most likely cause of the severe developmental delay and seizure activity in the proband, further enriching our phenotypic understanding of KCNB1 developmental encephalopathies.

Spreading depolarization (SD) causes a massive neuronal/glial depolarization, disturbs ionic homeostasis and deranges neuronal network function. The metabolic burden imposed by SD may also generate marked amounts of reactive oxygen species (ROS). Yet, proper optical tools are required to study this aspect with spatiotemporal detail. Therefore, we earlier generated transgenic redox indicator mice. They express in excitatory projection neurons the cytosolic redox-sensor roGFP, a reduction/oxidation sensitive green fluorescent protein which is ratiometric by excitation and responds reversibly to redox alterations. Using adult male roGFPc mice, we analyzed SD-related ROS production in CA1 stratum pyramidale of submerged slices. SD was induced by K⁺ microinjection, O₂ withdrawal or mitochondrial uncoupling (FCCP). The extracellular DC potential deflection was accompanied by a spreading wavefront of roGFP oxidation, confirming marked neuronal ROS generation. Hypoxia-induced SD was preceded by a moderate oxidation, which became intensified as the DC potential deflection occurred. Upon K⁺-induced SD, roGFP oxidation slowly recovered within 10-15 min in some slices. Upon FCCP-or hypoxia-induced SD, recovery was limited. Withdrawing extracellular Ca²⁺ markedly dampened the SD-related roGFP oxidation and improved its reversibility, confirming a key-role of neuronal Ca²⁺ load in SD-related ROS generation. Neither mitochondrial uncoupling, nor inhibition of NADPH oxidase or xanthine oxidase abolished the SD-related roGFP oxidation. Therefore, ROS generation during SD involves mitochondria as well as non-mitochondrial sources. This first-time analysis of SD-related ROS dynamics became possible based on quantitative redox imaging in roGFP mice, an advanced approach, which will contribute to further decipher the molecular understanding of SD in brain pathophysiology.

Astrocytes are crucial for the functioning of the nervous system as they maintain the ion homeostasis via volume regulation. Pathological states, such as amyotrophic lateral sclerosis (ALS), affect astrocytes and might even cause a loss of such functions. In this study, we examined astrocytic swelling/volume recovery in both the brain and spinal cord of the SOD1 animal model to determine the level of their impairment caused by the ALS-like pathology. Astrocyte volume changes were measured in acute brain or spinal cord slices during and after exposure to hyperkalemia. We then compared the results with alterations of extracellular space (ECS) diffusion parameters, morphological changes, expression of the Kir4.1 channel and the potassium concentration measured in the cerebrospinal fluid, to further disclose the link between potassium and astrocytes in the ALS-like pathology. Morphological analysis revealed astrogliosis in both the motor cortex and the ventral horns of the SOD1 spinal cord. The activated morphology of SOD1 spinal astrocytes was associated with the results from volume measurements, which showed decreased swelling of these cells during hyperkalemia. Furthermore, we observed lower shrinkage of ECS in the SOD1 spinal ventral horns. Immunohistochemical analysis then confirmed decreased expression of the Kir4.1 channel in the SOD1 spinal cord, which corresponded with the diminished volume regulation. Despite astrogliosis, cortical astrocytes in SOD1 mice did not show alterations in swelling nor changes in Kir4.1 expression, and we did not identify significant changes in ECS parameters. Moreover, the potassium level in the cerebrospinal fluid did not deviate from the physiological concentration. The results we obtained thus suggest that ALS-like pathology causes impaired potassium uptake associated with Kir4.1 downregulation in the spinal astrocytes, but based on our data from the cortex, the functional impairment seems to be independent of the morphological state.

Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in PSEN1 (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between PSEN1 mutations and neuronal excitability remains to be fully elucidated. This study examined iPSC-derived neurons (iNs) from fAD patients with PSEN1 mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both PSEN1 mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of PSEN1 mutations on neuronal excitability. Additionally, both PSEN1 backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis.

Retinitis Pigmentosa (RP) is a heterogenous group of inherited disorder, and its progression not only affects the retina but also the primary visual cortex. This manifests imbalances in the excitatory and inhibitory neurotransmission. Here, we investigated if changes in cortical functioning is linked to alterations in GABAergic population of neurons and its two important subsets, somatostatin (SST) and parvalbumin (PV) neuron in rd1 model of retinal degeneration (RD). We demonstrate marked decrease in the proportion of SST neurons in different layers of cortex whereas PV neurons were less affected. Moreover, we found reduced expression of glutamatergic thalamic afferents (VGLUT2) due to lack of visual activity. These results suggest PV neurons are likely recruited by the cortical circuitry to increase the inhibitory drive and compensate the disrupted inhibition-excitation balance. However, reduced SST expression perhaps results in weakening of stimulus selectivity. Delineating their functional role during RD will provide insights for acquisition of high-resolution vision thereby improving current state of vision restoration.

[This retracts the article DOI: 10.3389/fncel.2019.00061.].

Background: The impact of maternal surgery combined with general anesthesia on neuroinflammation and the development of learning and memory impairment in offspring remains unclear. This study utilized a pathogen-free laparotomy model to investigate these changes during the second trimester, as well as their response to anti-inflammatory therapy.

Methods: C57BL/6 pregnant mice at the 14.5-day embryo stage (E 14.5) were either exposed to sevoflurane anesthesia alone or underwent laparotomy procedure. The neuroinflammatory response was evaluated at 7, 14, 21, and 28 days postnatal (P7, P14, P21, P28). Tau phosphorylation and cognitive ability were assessed at P28 and P30, respectively. The impact of perioperative administration of ibuprofen (60 mg/kg) on these aforementioned changes was subsequently evaluated.

Results: In the laparotomy group, levels of inflammatory factors (IL-4, IL-8, IL-17A, TGF-β, M-CSF, CCL2) in the brains of offspring mice, including the cerebral cortex and hippocampus, remained consistently elevated from P7 to P28. At P14, while the majority of inflammatory cytokine has no statistical difference, there was still a significant reactivation of inflammatory cytokines observed in the frontal cortex and hippocampus at P28. Furthermore, abnormal phosphorylation of tau and deficits in learning and memory were observed at P28 and P30. Administration of perioperative ibuprofen led to improvements in cognitive performance, reduction of systemic inflammation, and inhibiting abnormal phosphorylation of tau in the frontal cortex and hippocampus.

Conclusion: Our findings indicate that cognitive dysfunction is correlated with elevated levels of inflammatory cytokines and tau phosphorylation. Cognitive impairment and tau phosphorylation after laparotomy can persist at least until P28. Anti-inflammatory medications have been shown to enhance cognitive function by rapidly reducing inflammation in the brain, while also impacting neurological changes. This discovery may have implications for the development of treatment strategies aimed at managing cognitive impairment in post-operative patients.

The increasing prevalence of neurodevelopmental disorders has highlighted the need for improved testing methods to determine developmental neurotoxicity (DNT) hazard for thousands of chemicals. This paper proposes the integration of organoid intelligence (OI); leveraging brain organoids to study neuroplasticity in vitro, into the DNT testing paradigm. OI brings a new approach to measure the impacts of xenobiotics on plasticity mechanisms - a critical biological process that is not adequately covered in current DNT in vitro assays. Finally, the integration of artificial intelligence (AI) techniques will further facilitate the analysis of complex brain organoid data to study these plasticity mechanisms.