Neuroscience
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Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a fatal motoneuron disorder in children with unknown etiology. The disease is caused by mutations in the IGHMBP2 gene, encoding a Super Family 1 (SF1)-type RNA/DNA helicase. IGHMBP2 is a cytosolic protein that binds to ribosomes and polysomes, suggesting a role in mRNA metabolism. ⋯ Fluorescence Recovery after Photobleaching (FRAP) studies revealed translational down-regulation of an eGFP-myr-β-actin 3'UTR mRNA in growth cones. Local translational regulation of β-actin mRNA was dependent on the 3' UTR but independent of direct Ighmbp2-binding to β-actin mRNA. Taken together, our data indicate that Ighmbp2 deficiency results in local but modest disruption of protein biosynthesis which might partially contribute to the motoneuron defects seen in SMARD1.
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Traumatic brain injury (TBI) results in mitochondrial dysfunction and induction of lipid peroxidation (LP). Lipid peroxidation-derived neurotoxic aldehydes such as 4-HNE and acrolein bind to mitochondrial proteins, inducing additional oxidative damage and further exacerbating mitochondrial dysfunction and LP. Mitochondria are heterogeneous, consisting of both synaptic and non-synaptic populations. ⋯ By 24 h, synaptic respiration is significantly impaired compared to synaptic sham, whereas non-synaptic respiration does not decline significantly until 48 h. Decreases in respiration are associated with increases in oxidative damage to synaptic and non-synaptic mitochondrial proteins at 48 h and 72 h, respectively. These results indicate that the therapeutic window for mitochondria-targeted pharmacological neuroprotectants to prevent respiratory dysfunction is shorter for the more vulnerable synaptic mitochondria than for the non-synaptic population.
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We previously demonstrated that the non-steroidal anti-inflammatory agent meloxicam has neuroprotective effects in an oxygen and glucose deprivation model (OGD) of rat organotypic hippocampal slice cultures. We wondered if GABAergic transmission changed the neuroprotective effects of meloxicam and if meloxicam was able to modulate endoplasmic reticulum stress (ER stress) in this model. Mortality was measured using propidium iodide. ⋯ However, in light of its effects on caspase 3 and PARP, bicuculline did not seem to promote the apoptotic pathway. Our results also showed that meloxicam modified the unfolded protein response (UPR), as well as the transcriptional response of different genes, including the GABAA receptor, alpha1, beta3 and gamma2 subunits. We concluded that meloxicam has a neuroprotective anti-apoptotic action, is able to enhance the UPR independently of the systemic anti-inflammatory response and its neuroprotective effect can be inhibited by blocking GABAA receptors.
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Although the neurobiological mechanisms underlying autism spectrum disorder (ASD) are still unknown, dysregulation of serotonergic systems has been implicated in the etiology of ASD, and serotonergic antidepressant drugs are often prescribed to treat some symptoms of ASD. The BALB/c strain of mice express a dysregulated serotonergic system and a phenotype that is relevant to ASD. In this study, juvenile male BALB/c mice were exposed to the selective serotonin reuptake inhibitor fluoxetine either chronically (18 mg/kg/day in drinking water, post-natal day (PND) 28-39) or acutely (18 mg/kg, i.p.; PND40), or to vehicle control conditions (0.9% sterile saline, i.p.; PND40), prior to being exposed to the three-chambered sociability test (SAT; PND40). ⋯ Acute fluoxetine decreased social behavior, while chronic fluoxetine increased social behavior compared with vehicle-treated controls. Furthermore, acute and chronic fluoxetine treatments were without effect on TPH2 activity but differentially affected populations of serotonergic neurons in the DR. These data are consistent with the hypothesis that serotonergic systems are implicated in social behavior that is relevant for ASD.
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The ventral tegmental area (VTA) is one of the origins of the brain dopaminergic system and is involved in regulating various physiological functions such as pain processing and motivation. In this study, we utilized a fiber photometry system to specifically investigate the activity of dopamine neurons in the VTA using dopamine transporter promoter-driven Cre recombinase-expressing mice and site-specific infection of adeno-associated virus carrying the FLEX G-CaMP6 gene. As expected, expression of G-CaMP6 was restricted to VTA dopamine neurons. ⋯ These stimuli resulted in a rapid and short-lasting increase in the activity of VTA dopamine neurons while the control stimuli of a gentle tail touch and appearance of empty box did not induce any changes. In addition, fluorescence intensity was not changed by any of these stimuli in the control animals expressing hrGFP instead of G-CaMP6 in VTA dopamine neurons. Our data clearly show that acute aversive stimuli rapidly increase the activity of VTA dopamine neurons and thus suggest a salience-processing role.