Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex.
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ABSTRACT:
SUBMITTER: Innocenzi E
PROVIDER: S-EPMC8261640 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neurexins are presynaptic cell-adhesion molecules essential for synaptic function that are expressed in thousands of alternatively spliced isoforms. Recent studies suggested that alternative splicing at splice site 4 (SS4) of Nrxn1 is tightly regulated by an activity-dependent mechanism. Given that Nrxn1 alternative splicing at SS4 controls NMDA-receptor-mediated synaptic responses, activity-dependent SS4 alternative splicing would suggest a new synaptic plasticity mechanism. However, conflicting results confound the assessment of neurexin alternative splicing, prompting us to re-evaluate this issue. We find that in cortical cultures, membrane depolarization by elevated extracellular K+-concentrations produced an apparent shift in Nrxn1-SS4 alternative splicing by inducing neuronal but not astroglial cell death, resulting in persistent astroglial Nrxn1-SS4+ expression and decreased neuronal Nrxn1-SS4- expression. in vivo, systemic kainate-induced activation of neurons in the hippocampus produced no changes in Nrxn1-SS4 alternative splicing. Moreover, focal kainate injections into the mouse cerebellum induced small changes in Nrxn1-SS4 alternative splicing that, however, were associated with large decreases in Nrxn1 expression and widespread DNA damage. Our results suggest that although Nrxn1-SS4 alternative splicing may represent a mechanism of activity-dependent synaptic plasticity, common procedures for testing this hypothesis are prone to artifacts, and more sophisticated approaches will be necessary to test this important question.
| S-EPMC7985251 | biostudies-literature
Project description:Aims: Recent research suggests that aerobic exercise can be performed safely within the first week following a concussion injury and that early initiation of exercise may speed recovery. To better understand the physiological changes during a concussion, we tested the hypothesis that mild-to-intense exercise testing can be performed within days immediately following injury, and can be used to discern differences between the concussed and normal healthy state. Thus, the purpose was to observe the cerebral hemodynamic responses to incremental exercise testing performed acutely post-concussion in high-performance athletes. Methods: This study was a within- and between-experimental design, with seven male university ice hockey teams participating. A subgroup of five players acted as control subjects (CON) and was tested at the same time as the 14 concussed (mTBI) players on Day 2, 4, and 7 post-concussion. A 5-min resting baseline and 5-min exercise bouts of mild (EX1), moderate (EX2), and high (EX3) intensity exercise were performed on a cycle ergometer. Near-infrared spectroscopy was used to monitor pre-frontal cortex oxy-haemoglobin (HbO2), deoxy-haemoglobin (HHb), and total blood volume (tHb) changes. Results: ANOVA compared differences between testing days and groups, and although large percentage changes in HbO2 (20-30%), HHb (30-40%), and tHb (30-40%) were recorded, no significant (p ? 0.05) differences in cerebral hemodynamics occurred between mTBI vs. CON during aerobic exercise testing on any day post-injury. Furthermore, there was a linear relationship between exercise intensity vs. cerebral hemodynamics during testing for each day (r 2 = 0.83-0.99). Conclusion: These results demonstrate two novel findings: (1) mild-to-intense aerobic exercise testing can be performed safely as early as Day 2 post-concussion injury in a controlled laboratory environment; and (2) evidence-based objective measures such as cerebral hemodynamics can easily be collected using near-infrared spectroscopy (NIRS) to monitor physiological changes during the first-week post-injury. This research has important implications for monitoring physiological recovery post-injury and establishing new rehabilitation guidelines.
| S-EPMC7028689 | biostudies-literature
Project description:AMPA- and NMDA-type glutamate receptors mediate distinct postsynaptic signals that differ characteristically among synapses. How postsynaptic AMPA- and NMDA-receptor levels are regulated, however, remains unclear. Using newly generated conditional knockin mice that enable genetic control of neurexin alternative splicing, we show that in hippocampal synapses, alternative splicing of presynaptic neurexin-1 at splice site 4 (SS4) dramatically enhanced postsynaptic NMDA-receptor-mediated, but not AMPA-receptor-mediated, synaptic responses without altering synapse density. In contrast, alternative splicing of neurexin-3 at SS4 suppressed AMPA-receptor-mediated, but not NMDA-receptor-mediated, synaptic responses, while alternative splicing of neurexin-2 at SS4 had no effect on NMDA- or AMPA-receptor-mediated responses. Presynaptic overexpression of the neurexin-1β and neurexin-3β SS4+ splice variants, but not of their SS4- splice variants, replicated the respective SS4+ knockin phenotypes. Thus, different neurexins perform distinct nonoverlapping functions at hippocampal synapses that are independently regulated by alternative splicing. These functions transsynaptically control NMDA and AMPA receptors, thereby mediating presynaptic control of postsynaptic responses.
| S-EPMC6554035 | biostudies-literature
Project description:The process of memory consolidation requires transcription and translation to form long-term memories. Significant effort has been dedicated to understanding changes in hippocampal gene expression after contextual fear conditioning. However, alternative splicing by differential transcript regulation during this time period has received less attention. Here, we use RNA-seq to determine exon-level changes in expression after contextual fear conditioning and retrieval. Our work reveals that a short variant of Homer1, Ania-3, is regulated by contextual fear conditioning. The ribosome biogenesis regulator Las1l, small nucleolar RNA Snord14e, and the RNA-binding protein Rbm3 also change specific transcript usage after fear conditioning. The changes in Ania-3 and Las1l are specific to either the new context or the context-shock association, while the changes in Rbm3 occur after context or shock only. Our analysis revealed novel transcript regulation of previously undetected changes after learning, revealing the importance of high throughput sequencing approaches in the study of gene expression changes after learning.
| S-EPMC5028328 | biostudies-literature
Project description:We analysed changes in transcript levels and alternative splicing in the temporal cortex of individuals of different ages that were cognitively normal, affected by frontotemporal lobar degeneration (FTLD), or affected by Alzheimer's disease (AD). Our experiment's purpose is to provide new insights into the gene expression changes that distinguish healthy aging from neurodegeneration and identify the candidate regulators of alternative splicing that are associated with both processes.
2012-04-27 | E-MTAB-656 | biostudies-arrayexpress
Project description:BackgroundSam68, an RNA-binding protein, exerts oncogenic functions in several types of cancer. However, the specific functions and mechanisms of Sam68 in colorectal cancer (CRC) had not been previously clarified. Pyruvate kinase muscle (PKM)2 is the key rate-limiting enzyme in glycolysis, and PKM2 maintains the glycolysis-dominant energy metabolism in most cancer cells.MethodsCCK8 assay was performed to show the effect of Sam68 on cell growth. Pyruvate kinase activity and lactate detection assays were performed to analyze the effects of Sam68 on aerobic glycolysis. RNA immunoprecipitation (RIP) was used to detect the binding of Sam68 to the PKM2 sequence. Western blot and real-time PCR were executed to analyze the regulation of PKM2 by Sam68.ResultsGain-of-function and loss-of-function studies showed that ectopic expression of Sam68 promoted glycolysis and cell proliferation in CRC cells, whereas Sam68 knockdown inhibited glycolysis and cell proliferation. Mechanically, Sam68 modulated the expression profile of pyruvate kinase (PKM2 or PKM1) by regulating its alternative splicing. Overexpression of Sam68 was associated with decreased PKM1/PKM2 ratio, which positively contributed to the glycolysis procedure. Sam68 significantly promoted cell proliferation and caused a decrease of PKM1/PKM2 ratio, resulting in the metabolism of glucose switched from oxidative phosphorylation to glycolysis in CRC cells. Besides, Sam68 enhanced PKM2 mRNA transport from the nucleus to cytoplasm and increased the expression of PKM2 protein, resulting in elevated pyruvate kinase activity and lactate production.ConclusionsThese findings suggested that Sam68 affected cell growth and glycolysis pathway by regulating the alternative splicing and expression of PKM2 in CRC.
| S-EPMC7210197 | biostudies-literature
Project description:A T-cell-independent (TI) pathway activated by microbiota results in the generation of low-affinity homeostatic IgA with a critical role in intestinal homeostasis. Moderate aerobic exercise (MAE) provides a beneficial impact on intestinal immunity, but the action of MAE on TI-IgA generation under senescence conditions is unknown. This study aimed to determine the effects of long-term MAE on TI-IgA production in young (3 month old) BALB/c mice exercised until adulthood (6 months) or aging (24 months). Lamina propria (LP) from the small intestine was obtained to determine B cell and plasma cell sub-populations by flow cytometry and molecular factors related to class switch recombination [Thymic Stromal Lymphopoietin (TSLP), A Proliferation-Inducing Ligand (APRIL), B Cell Activating Factor (BAFF), inducible nitric oxide synthase (iNOS), and retinal dehydrogenase (RDH)] and the synthesis of IgA [α-chain, interleukin (IL)-6, IL-21, and Growth Factor-β (TGF-β)]; and epithelial cells evaluated IgA transitosis [polymeric immunoglobulin receptor (pIgR), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-4] by the RT-qPCR technique. The results were compared with data obtained from sedentary age-matched mice. Statistical analysis was computed with ANOVA, and p < 0.05 was considered to be a statistically significant difference. Under senescence conditions, MAE promoted the B cell and IgA+ B cells and APRIL, which may improve the intestinal response and ameliorate the inflammatory environment associated presumably with the downmodulation of pro-inflammatory mediators involved in the upmodulation of pIgR expression. Data suggested that MAE improved IgA and downmodulate the cytokine pro-inflammatory expression favoring homeostatic conditions in aging.
| S-EPMC11311420 | biostudies-literature
Project description:The neuropeptide oxytocin (OXT) has generated considerable interest as potential treatment for psychiatric disorders, including anxiety and autism spectrum disorders. However, the behavioral and molecular consequences associated with chronic OXT treatment and chronic receptor (OXTR) activation have scarcely been studied, despite the potential therapeutic long-term use of intranasal OXT. Here, we reveal that chronic OXT treatment over two weeks increased anxiety-like behavior in rats, with higher sensitivity in females, contrasting the well-known anxiolytic effect of acute OXT. The increase in anxiety was transient and waned 5 days after the infusion has ended. The behavioral effects of chronic OXT were paralleled by activation of an intracellular signaling pathway, which ultimately led to alternative splicing of hypothalamic corticotropin-releasing factor receptor 2α (Crfr2α), an important modulator of anxiety. In detail, chronic OXT shifted the splicing ratio from the anxiolytic membrane-bound (mCRFR2α) form of CRFR2α towards the soluble CRFR2α (sCRFR2α) form. Experimental induction of alternative splicing mimicked the anxiogenic effects of chronic OXT, while sCRFR2α-knock down reduced anxiety-related behavior of male rats. Furthermore, chronic OXT treatment triggered the release of sCRFR2α into the cerebrospinal fluid with sCRFR2α levels positively correlating with anxiety-like behavior. In summary, we revealed that the shifted splicing ratio towards expression of the anxiogenic sCRFR2α underlies the adverse effects of chronic OXT treatment on anxiety.
| S-EPMC10914602 | biostudies-literature
Project description:Age-associated cardiovascular (CV) dysfunction, namely arterial dysfunction, is a key antecedent to the development of CV disease (CVD). Arterial dysfunction with aging is characterized by impaired vascular endothelial function and stiffening of the large elastic arteries, each of which is an independent predictor of CVD. These processes are largely mediated by an excess production of reactive oxygen species (ROS) and an increase in chronic, low-grade inflammation that ultimately leads to a reduction in bioavailability of the vasodilatory molecule nitric oxide. Additionally, there are other fundamental aging mechanisms that may contribute to excessive ROS and inflammation termed the "hallmarks of aging"; these additional mechanisms of arterial dysfunction may represent therapeutic targets for improving CV health with aging. Aerobic exercise is the most well-known and effective intervention to prevent and treat the effects of aging on CV dysfunction. However, the majority of mid-life and older (ML/O) adults do not meet recommended exercise guidelines due to traditional barriers to aerobic exercise, such as reduced leisure time, motivation, or access to fitness facilities. Therefore, it is a biomedical research priority to develop and implement time- and resource-efficient alternative strategies to aerobic exercise to reduce the burden of CVD in ML/O adults. Alternative strategies that mimic or are inspired by aerobic exercise, that target pathways specific to the fundamental mechanisms of aging, represent a promising approach to accomplish this goal.
| S-EPMC10068966 | biostudies-literature
Project description:BackgroundAerobic exercise is associated with enhanced plasticity in the motor cortex of healthy individuals, but the effect of aerobic exercise on neuroplasticity following a stroke is unknown.ObjectiveThe aim of this study was to compare corticomotoneuronal excitability and neuroplasticity in the upper limb cortical representation following a single session of low intensity lower limb cycling, or a rest control condition.MethodsWe recruited chronic stroke survivors to take part in three experimental conditions in a randomised, cross-over design. Corticomotoneuronal excitability was examined using transcranial magnetic stimulation to elicit motor evoked potentials in the affected first dorsal interosseus muscle. Following baseline measures, participants either cycled on a stationary bike at a low exercise intensity for 30 minutes, or remained resting in a seated position for 30 minutes. Neuroplasticity within the motor cortex was then examined using an intermittent theta burst stimulation (iTBS) paradigm. During the third experimental condition, participants cycled for the 30 minutes but did not receive any iTBS.ResultsTwelve participants completed the study. We found no significant effect of aerobic exercise on corticomotoneuronal excitability when compared to the no exercise condition (P > 0.05 for all group and time comparisons). The use of iTBS did not induce a neuroplastic-like response in the motor cortex with or without the addition of aerobic exercise.ConclusionsOur results suggest that following a stroke, the brain may be less responsive to non-invasive brain stimulation paradigms that aim to induce short-term reorganisation, and aerobic exercise was unable to induce or improve this response.
| S-EPMC4809484 | biostudies-literature