Neuronal activity orchestrates the proper development of the neuronal circuitry by regulating both transcriptional and post‐transcriptional gene expression programmes. How these programmes are ...coordinated, however, is largely unknown. We found that the transcription of miR379–410, a large cluster of brain‐specific microRNAs (miRNAs), is induced by increasing neuronal activity in primary rat neurons. Results from chromatin immunoprecipitation and luciferase reporter assays suggest that binding of the transcription factor myocyte enhancing factor 2 (Mef2) upstream of miR379–410 is necessary and sufficient for activity‐dependent transcription of the cluster. Mef2‐induced expression of at least three individual miRNAs of the miR379–410 cluster is required for activity‐dependent dendritic outgrowth of hippocampal neurons. One of these miRNAs, the dendritic miR‐134, promotes outgrowth by inhibiting translation of the mRNA encoding for the translational repressor Pumilio2. In summary, we have described a novel regulatory pathway that couples activity‐dependent transcription to miRNA‐dependent translational control of gene expression during neuronal development.
The E3 ubiquitin ligase Ube3a is an important regulator of activity-dependent synapse development and plasticity. Ube3a mutations cause Angelman syndrome and have been associated with autism spectrum ...disorders (ASD). However, the biological significance of alternative Ube3a transcripts generated in mammalian neurons remains unknown. We report here that Ube3a1 RNA, a transcript that encodes a truncated Ube3a protein lacking catalytic activity, prevents exuberant dendrite growth and promotes spine maturation in rat hippocampal neurons. Surprisingly, Ube3a1 RNA function was independent of its coding sequence but instead required a unique 3' untranslated region and an intact microRNA pathway. Ube3a1 RNA knockdown increased activity of the plasticity-regulating miR-134, suggesting that Ube3a1 RNA acts as a dendritic competing endogenous RNA. Accordingly, the dendrite-growth-promoting effect of Ube3a1 RNA knockdown in vivo is abolished in mice lacking miR-134. Taken together, our results define a noncoding function of an alternative Ube3a transcript in dendritic protein synthesis, with potential implications for Angelman syndrome and ASD.
Synaptic downscaling is a homeostatic mechanism that allows neurons to reduce firing rates during chronically elevated network activity. Although synaptic downscaling is important in neural circuit ...development and epilepsy, the underlying mechanisms are poorly described. We performed small RNA profiling in picrotoxin (PTX)‐treated hippocampal neurons, a model of synaptic downscaling. Thereby, we identified eight microRNAs (miRNAs) that were increased in response to PTX, including miR‐129‐5p, whose inhibition blocked synaptic downscaling in vitro and reduced epileptic seizure severity in vivo. Using transcriptome, proteome, and bioinformatic analysis, we identified the calcium pump Atp2b4 and doublecortin (Dcx) as miR‐129‐5p targets. Restoring Atp2b4 and Dcx expression was sufficient to prevent synaptic downscaling in PTX‐treated neurons. Furthermore, we characterized a functional crosstalk between miR‐129‐5p and the RNA‐binding protein (RBP) Rbfox1. In the absence of PTX, Rbfox1 promoted the expression of Atp2b4 and Dcx. Upon PTX treatment, Rbfox1 expression was downregulated by miR‐129‐5p, thereby allowing the repression of Atp2b4 and Dcx. We therefore identified a novel activity‐dependent miRNA/RBP crosstalk during synaptic scaling, with potential implications for neural network homeostasis and epileptogenesis.
Synopsis
A systematic approach using small RNA and mRNA profiling in combination with proteomics is used to delineate post‐transcriptional regulatory pathways involved in synaptic scaling. This led to the identification of a pathway consisting of the miRNA miR‐129‐5p and the RNA‐binding protein Rbfox that controls excitatory synapse function in neurons and epileptic seizure activity in the brain.
8 microRNAs, including miR‐129‐5p, are upregulated during homeostatic synaptic downscaling in hippocampal neurons.
miR‐129‐5p inhibition blocks synaptic downscaling in vitro and kainic acid‐induced epileptic seizures in vivo.
A combination of transcriptomics, proteomics and bioinformatics was used to identify miR‐129‐5p target mRNAs, including Atp2b4, Dcx and Rbfox1/3.
Activity‐dependent downregulation of Rbfox1 by miR‐129‐5p is required for the repression of synaptic genes during homeostatic synaptic downscaling.
Combining miRNA and mRNA profiling with proteomics reveals roles for miR‐129‐5p and the RNA‐binding protein Rbfox in excitatory synapse function and epileptic seizure.
Technetium-99m sestamibi single-photon emission computed tomography/computed tomography (
99m
Tc-sestamibi SPECT/CT) is a mainstay of the pre-operative localization of parathyroid lesions. We report ...here the case of a 30 year-old woman with a fortuitously discovered 2 cm cervical mass for which a parathyroid origin was originally suspected due to its retro-thyroidal localization and a personal history of nephrolithiasis. Normal serum calcium and parathyroid hormone (PTH) levels excluded primary hyperparathyroidism, raising suspicion of a non-functional parathyroid adenoma, and SPECT/CT imaging showed that the mass was
99m
Tc-sestamibi-avid. Fine-needle aspiration (FNA) was performed; cytology was non-diagnostic but the needle washout was negative for thyroglobulin, calcitonin and PTH, arguing against a thyroidal or parathyroidal origin of the mass. Core needle biopsy revealed a schwannoma, ostensibly originating from the recurrent laryngeal nerve; upon surgical resection, it was finally found to arise from the esophageal submucosa. This case illustrates the fact that endocrinologists, radiologists, nuclear medicine, head and neck, and other specialists investigating patients with cervical masses should be aware that schwannomas need to be considered in the differential diagnosis of focal
99m
Tc-sestamibi uptake in the neck region.
The proper development and function of neuronal circuits rely on a tightly regulated balance between excitatory and inhibitory (E/I) synaptic transmission, and disrupting this balance can cause ...neurodevelopmental disorders, for example, schizophrenia. MicroRNA-dependent gene regulation in pyramidal neurons is important for excitatory synaptic function and cognition, but its role in inhibitory interneurons is poorly understood. Here, we identify
as a regulator of short-term memory and inhibitory synaptic transmission in the mouse hippocampus. Sponge-mediated
inactivation specifically in mouse parvalbumin (PV)-expressing interneurons impairs spatial recognition memory and enhances GABAergic synaptic input onto pyramidal neurons. Cellular and behavioral phenotypes associated with
inactivation are paralleled by an upregulation of the schizophrenia (SCZ)-associated
, which we validated as a direct
target gene. Our findings suggest that
is a critical regulator of PV interneuron function in mice, with implications for cognition and SCZ. More generally, they provide evidence that microRNAs orchestrate neural circuit development by fine-tuning both excitatory and inhibitory synaptic transmission.
Introduction Consumptive hypothyroidism is a rare paraneoplastic condition most commonly associated with infantile hemangiomas. It is caused by overexpression of deiodinase type 3 (D3), which leads ...to preferential conversion of thyroxine to the metabolically inactive reverse triiodothyronine (rT3), paralleled by a decrease of the biologically active T3. Case presentation A 46-year-old male patient with previously normal thyroid function was diagnosed with a renal carcinoma with rhabdoid differentiation. He was treated with sunitinib, followed by the immune checkpoint inhibitors ipilimumab and nivolumab, and he developed primary hypothyroidism secondary to thyroiditis. Substitution with unusually high doses of levothyroxine as high as 4.3 µg/kg/day did not normalize his thyroid function. Poor compliance was refuted because there was no improvement after observed administration. He had no malabsorption. Although tyrosine kinase inhibitors can increase the expression of D3, this effect tends to be modest. Therefore, the suspicion of tumor-related consumptive hypothyroidism was raised and supported by low free T3 and elevated rT3 levels. The therapy could not be further modified because the patient opted for palliative care and passed away 12 days later. Immunohistochemistry of the tumor from a sample obtained prior to systemic therapy documented abundant expression of D3, corroborating the diagnosis of consumptive hypothyroidism. Conclusions This observation extends the spectrum of malignancies overexpressing D3. Although rare, increased awareness of this paraneoplastic syndrome is key, if persistent hypothyroidism cannot be explained by compliance issues or malabsorption. Substitution with high doses of levothyroxine, and combination therapy with liothyronine, can correct hypothyroidism in these patients.
Chemorepulsion by semaphorins plays a critical role during the development of neuronal projections. Although semaphorin-induced chemoattraction has been reported in vitro, the contribution of this ...activity to axon pathfinding is still unclear. Using genetic and culture models, we provide evidence that both attraction and repulsion by Sema3B, a secreted semaphorin, are critical for the positioning of a major brain commissural projection, the anterior commissure (AC). NrCAM, an immunoglobulin superfamily adhesion molecule of the L1 subfamily, associates with neuropilin-2 and is a component of a receptor complex for Sema3B and Sema3F. Finally, we show that activation of the FAK/Src signaling cascade distinguishes Sema3B-mediated attractive from repulsive axonal responses of neurons forming the AC, revealing a mechanism underlying the dual activity of this guidance cue.
Skeletal muscle is a plastic and complex tissue, rich in proteins that are subject to continuous rearrangements. Skeletal muscle homeostasis can be affected by different types of stresses, including ...physical activity, a physiological stressor able to stimulate a robust increase in different heat shock proteins (HSPs). The modulation of these proteins appears to be fundamental in facilitating the cellular remodeling processes related to the phenomenon of training adaptations such as hypertrophy, increased oxidative capacity, and mitochondrial activity. Among the HSPs, a special attention needs to be devoted to Hsp60 and αB-crystallin (CRYAB), proteins constitutively expressed in the skeletal muscle, where their specific features could be highly relevant in understanding the impact of different volumes of training regimes on myofiber types and in explaining the complex picture of exercise-induced mechanical strain and damaging conditions on fiber population. This knowledge could lead to a better personalization of training protocols with an optimal non-harmful workload in populations of individuals with different needs and healthy status. Here, we introduce for the first time to the reader these peculiar HSPs from the perspective of exercise response, highlighting the control of their expression, biological function, and specific distribution within skeletal muscle fiber-types.
Uricemia has been identified as an independent risk factor for cardiovascular disease. In the general population, hyperuricemia is associated with hypertension, endothelial dysfunction, and other ...cardiovascular risk (CVR) factors. Our aim was to explore the prevalence of hyperuricemia among Olympic athletes, evaluating the influence of sporting discipline and its correlation with CVR factors. We enrolled 1173 Olympic athletes classified into four disciplines: power, skill, endurance, and mixed. Clinical, anthropometric data, and complete blood test results were collected. Hyperuricemia was present in 4.4% of athletes, 0.3% were hypertensive, 11.7% had high-normal blood pressure values, 0.2% were diabetic, 1.2%. glucose intolerance, 8.2% active smokers, and 3% were obese. Males had a higher prevalence of hyperuricemia (5.3%) than females (3.4%) with no significant differences between different sporting disciplines (male,
= 0.412; female
= 0.561). Males with fat mass >22% presented higher uricemia (5.8 ± 1 vs. 5.3 ± 1 mg/dL,
= 0.010) like hypertensive athletes (6.5 ± 0.3 vs. 5.3 ± 1 mg/dL,
= 0.031), those with high-normal blood pressure (5.13 ± 1 vs. 4.76 ± 1.1 mg/dL,
= 0.0004) and those with glucose intolerance (6 ± 0.8 vs. 5.3 ± 1 mg/dL,
= 0.066). The study provides a comprehensive evaluation of hyperuricemia among Olympic athletes, revealing a modest prevalence, lower than in the general population. However, aggregation of multiple CVR factors could synergistically elevate the risk profile, even in a population assumed to be at low risk. Therefore, uric acid levels should be monitored as part of the CVR assessment in athletes.
Conflicting results on the cardiovascular involvement after SARS-CoV-2 infection generated concerns on the safety of return-to-play (RTP) in athletes. The aim of this study was to evaluate the ...prevalence of cardiac involvement after COVID-19 in Olympic athletes, who had previously been screened in our pre-participation program. Since November 2020, all consecutive Olympic athletes presented to our Institute after COVID-19 prior to RTP were enrolled. The protocol was dictated by the Italian governing bodies and comprised: 12-lead ECG, blood test, cardiopulmonary exercise test (CPET), 24-h ECG monitoring, and spirometry. Cardiovascular Magnetic Resonance (CMR) was also performed. All Athletes were previously screened in our Institute as part of their periodical pre-participation evaluation. Forty-seven Italian Olympic athletes were enrolled: 83% asymptomatic, 13% mildly asymptomatic, and 4% had pneumonia. Uncommon premature ventricular contractions (PVCs) were found in 13% athletes; however, only 6% (n = 3) were newly detected. All newly diagnosed uncommon PVCs were detected by CPET. One of these three athletes had evidence for acute myocarditis by CMR, along with Troponin raise; another had pericardial effusion. No one of the remaining athletes had abnormalities detected by CMR. Cardiac abnormalities in Olympic athletes screened after COVID-19 resolution were detected in a minority, and were associated with new ventricular arrhythmias. Only one had evidence for acute myocarditis (in the presence of symptoms and elevated biomarkers). Our data support the efficacy of the clinical assessment including exercise-ECG to raise suspicion for cardiovascular abnormalities after COVID-19. Instead, the routine use of CMR as a screening tool appears unjustified.
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