Synapse最新文献

The accumulation of tau tangles and Aβ plaques are prominent neuropathologies that characterize Alzheimer's disease (AD) and Down syndrome (DS). Continuous developments of PET tracers as biomarkers can be supported by autoradiography to validate effectiveness and accuracy of binding properties that elucidate the pathophysiology of DSAD and AD. This in vitro comparative study evaluates [¹²⁵I]IPPI binding to tau and [¹²⁵I]IBETA binding to Aβ plaques in the frontal cortex (FCX) and temporal cortex (TCX) of postmortem human brain slices of AD (n = 5), DSAD (n = 5), and cognitively normal (CN) (n = 5) cases. With anti-tau and anti-Aβ immunostains confirming the presence of tau and Aβ plaques, [¹²⁵I]IPPI and [¹²⁵I]IBETA binding in autoradiographic images were significantly higher in DSAD and AD gray matter (GM) compared to CN. When comparing DSAD with AD, FCX and TCX GM binding was similar throughout DSAD and AD, except in FCX GM where there was 48% more [¹²⁵I]IPPI binding in DSAD than AD. In vitro drug inhibition studies revealed that [¹²⁵I]IPPI binding was significantly inhibited with increasing harmine concentrations (IC₅₀ = 115 nM) in DSAD FCX and TCX, but KuFal194, a DYRK1A drug, minimally inhibited [¹²⁵I]IPPI binding in the same cases. The GM/white matter ratios for DSAD ([¹²⁵I]IPPI = 4.1, [¹²⁵I]IBETA = 2.9) and AD ([¹²⁵I]IPPI = 4.2, [¹²⁵I]IBETA = 2.6) were significantly greater than CN ([¹²⁵I]IPPI = 1.3, [¹²⁵I]IBETA = 1.2). A positive correlation between [¹²⁵I]IPPI and [¹²⁵I]IBETA binding suggests a synergistic relationship between tau and Aβ plaque in DSAD and AD pathology. This study demonstrates that [¹²⁵I]IPPI and [¹²⁵I]IBETA may serve as novel radiotracers in both DSAD and AD to continue diagnostic investigations.

Propofol (PPF), a commonly employed clinical anesthetic, has elicited growing concern due to its associated neurotoxic effects. However, the functional role and mechanistic insights of microRNA-3909 (miR-3909) in PPF-induced neurotoxicity remain unexplored. This study sought to elucidate the expression of miR-3909 and its underlying molecular mechanisms in the context of PPF-induced neurotoxicity. An in vitro model of  PPF neurotoxicity was established using SH-SY5Y cells (PPF-SH-SY5Y). Initial assessments via cell counting kit-8 (CCK-8) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) demonstrated that treatment with 50 µM PPF significantly reduced cell viability and downregulated miR-3909 expression. Subsequent functional assays revealed that overexpression of miR-3909 effectively alleviated PPF-induced neurotoxicity, as evidenced by enhanced cell viability, suppression of apoptosis, reduced lactate dehydrogenase (LDH) release, and decreased reactive oxygen species (ROS) levels. Mechanistic investigations, including a dual-luciferase reporter assay, validated that miR-3909 directly targets and negatively regulates the expression of polymerase I and transcript release factor (PTRF). Notably, PTRF was significantly upregulated in PPF-SH-SY5Y cells, and overexpression of PTRF substantially counteracted the neuroprotective effects mediated by miR-3909. Collectively, these findings indicate that miR-3909 alleviates propofol-induced neurotoxicity by targeting PTRF, thereby providing a potential therapeutic target for this condition.

To investigate the regulatory mechanism of BLACAT1 expression in sevoflurane (Sev)-induced neuronal cell injury. An in vitro model was created by treating microglial cell lines with 3% Sev. An in vivo model was created by administering 2.2% Sev gas inhalation to mice for three consecutive days. Learning and memory capacity was assessed using the Morris water maze test. Gene expression was detected via RT-qPCR, while cellular functional alterations were observed through CCK-8 assays and flow cytometry. ELISA monitored inflammatory cytokine levels, while assay kits assessed oxidative stress marker expression. Dual luciferase reporter assay and RNA immunoprecipitation validated gene-target relationships. Treatment with Sev increased BLACAT1 levels in microglia and mouse hippocampi, while reducing the expression of miR-361-3p. Transfection with si-BLACAT1 counteracted the inhibitory effects of Sev on cell proliferation while reducing inflammatory and oxidative stress levels. miR-361-3p was a downstream target of BLACAT1, with miR inhibitor counteracting si-BLACAT1's protective effects on damaged neurons. Furthermore, Sev treatment impaired learning and memory functions in the mouse hippocampus, as evidenced by prolonged escape latency and fewer platform crossings during the original platform phase. BLACAT1 participates in Sev-induced glial cell injury via miR-361-3p, leading to hippocampal cognitive dysfunction.

Low-dose ketamine is an efficacious antidepressant for treatment-resistant unipolar and bipolar depressed patients. Major depressive disorder patients receiving a single infusion report elevated mood within 2 h, and ketamine's antidepressant effects have been observed as long as 7 days posttreatment. In light of this remarkable observation, efforts have been undertaken to "reverse-translate" ketamine's effects to understand its mechanism of action. Major advances have been achieved in understanding the molecular, cellular, and circuit-level changes that are initiated by low-dose ketamine. Although enhancement of protein synthesis clearly plays a role, the field lacks a comprehensive understanding of the protein synthesis program initiated after ketamine treatment. Here, using ribosome-bound mRNA footprinting and deep sequencing (RiboSeq), we uncovered a genome-wide set of actively translated mRNAs (the translatome) in medial prefrontal cortex after an acute antidepressant-like dose of ketamine. Gene Ontology analysis confirmed that initiation of protein synthesis is a defining feature of antidepressant-dose ketamine in mice, and Gene Set Enrichment Analysis pointed to a role for GPCR signaling, metabolism, vascularization, and structural plasticity in ketamine's effects. One gene, VIPR2, whose protein product VPAC2 acts as a GPCR for the neuropeptide vasoactive intestinal peptide, was characterized in the cortex and identified as a potential novel target for antidepressant action. We demonstrate that VPAC2's functional expression in medial prefrontal cortex is limited to somatostatin-positive neurons and that in vivo dosing of a VPAC2 agonist elicits complex effects on prefrontal cortical pyramidal neurons, bidirectionally modulating their activity and disrupting the structure of coordinated neural activity. Finally, we show that VPAC2 agonism is sufficient to drive an antidepressant response, confirming the validity of our approach to targeted drug development.

Ketamine is widely used in pediatric anesthesia, but it may induce cortical neuronal damage, leading to apoptosis, neurofibrillary degeneration, and even cell death. miRNAs can regulate the neurotoxicity induced by ketamine in hippocampal neurons. This article explores the role of miR-378a-3p in ketamine-induced impairments, providing a reference for preventing hippocampal neurodegenerative lesions induced by anesthesia. The expression of miR-378a-3p and AdipoR1 was detected in hippocampal tissues and HT22 cells. To confirm the targeting interaction between miR-378a-3p and AdipoR1, dual-luciferase reporter assays were performed. Cellular viability and apoptosis were also assessed. Ketamine upregulates the expression of miR-378a-3p and downregulates the expression of AdipoR1 in hippocampal tissues and cells, impairing cognitive function in rats. Following ketamine induction, the levels of TNF-α, IL-1β, IL-6, caspase-3, ROS, and MDA are increased, while the level of SOD is decreased in rat hippocampal tissues and cells. Knocking down miR-378a-3p inhibits oxidative stress injury and the release of inflammatory factors by upregulating the expression of AdipoR1. These findings indicate that inhibition of miR-378a-3p protects hippocampal neurons from ketamine-induced damage by upregulating AdipoR1.This suggests that inhibiting miR-378a-3p protects hippocampal neuronal cells from Ketamine-induced damage by upregulating AdipoR1. The study indicates that miR-378a-3p/AdipoR1 axis is a crucial pathway regulating ketamine-induced cognitive impairments and hippocampal neurodegenerative lesions.

Postherpetic neuralgia (PHN) is a form of neuropathic pain that has significant detrimental effects. This study seeks to explore the potential association between miR-138-5p and PHN. A PHN model was established by infecting rats with the varicella-zoster virus. Following this, the expression level of miR-138-5p in spinal cord was quantified using RT-qPCR. To further investigate its role, miR-138-5p levels were modulated through the intrathecal administration of a lentivirus. The abnormal pain sensitivity in the rats was assessed utilizing the paw withdrawal threshold (PWT). Additionally, the levels of glial fibrillary acidic protein (GFAP) and pro-inflammatory cytokines (IL-1β and TNF-α) in spinal cord were measured by RT-qPCR or enzyme-linked immunosorbent assay (ELISA). Dual-luciferase reporter assay was used to verify the binding relationship between miR-138-5p and ROCK2. miR-138-5p is downregulated in the spinal cord tissue of PHN rats. Notably, the overexpression of miR-138-5p significantly enhances the PWT in PHN rats. Furthermore, the elevation of miR-138-5p markedly mitigates the abnormal increase of GFAP and pro-inflammatory factors. Mechanistically, ROCK2 has been identified as a downstream target of miR-138-5p. During the onset of PHN, ROCK2 is persistently upregulated, whereas the overexpression of miR-138-5p effectively inhibits this increase. Interestingly, the concurrent overexpression of miR-138-5p and ROCK2 can counteract the enhancement in PWT engendered solely by the upregulation of miR-138-5p, alongside the reduction in levels of GFAP, IL-1β, and IL-6. miR-138-5p plays a crucial role in modulating the development of PHN. In the context of PHN, miR-138-5p inhibits spinal cord inflammation and hyperalgesia by suppressing ROCK2.

Obsessive-compulsive disorder (OCD) is a chronic and debilitating psychiatric condition characterized by persistent, intrusive thoughts (obsessions) and repetitive ritualistic behaviors (compulsions). Accumulating evidence suggests that individuals with OCD demonstrate marked cognitive impairments, especially in executive function domains, including cognitive flexibility and working memory. Although existing therapeutic approaches (e.g., serotonin reuptake inhibitors and cognitive-behavioral therapy) can partially mitigate behavioral symptoms, their effectiveness in improving cognitive impairments remains limited. Although dopaminergic dysregulation has been implicated in OCD, the involvement of dopamine transporter (DAT) polymorphisms in cognitive flexibility and working memory impairments remains unclear, limiting the development of targeted therapeutic interventions. Although current investigations predominantly focus on dopamine (DA) D1/D2 receptors and serotonin transporters, the contribution of the DAT to OCD pathophysiology remains insufficiently explored. In the present study, we utilized Sapap3 knockout (KO) mice as a preclinical OCD model to examine dopaminergic dysregulation. Using ELISA, we conducted systematic comparisons of both dopaminergic levels and DAT expression between Sapap3 KO and wild-type (WT) mice. Additionally, we implemented targeted epigenetic modulation via histone acetylation in the nucleus accumbens (NAc) of Sapap3 KO mice. Our data demonstrated a significant decrease in DAT expression in the NAc of Sapap3 KO mice compared to WT (p = 0.0019). Strikingly, the administration of the histone deacetylase inhibitor 4-phenylbutyric acid (PBA) normalized DAT expression in KO mice to levels statistically equivalent to WT mice (p = 0.1107), achieving complete functional recovery of DAT deficiency. This restoration of DAT expression (p = 0.1107 PBA vs. WT) was accompanied by a significant reduction in the abnormally elevated baseline DA levels in Sapap3 KO mice (pretreatment: 192.46 ± 6.69 pg/mg; posttreatment: 173.67 ± 4.10 pg/mg, p < 0.01), which consequently improved executive function impairments. Our findings demonstrate that DAT polymorphisms represent a previously unrecognized pathogenic factor in cognitive impairment associated with OCD. Investigations of histone acetylation regulatory mechanisms revealed that changes in histone acetylation levels directly regulate DAT expression. We provide mechanistic evidence showing that epigenetic regulation of DAT expression can effectively reverse these neurological deficits, particularly through modulation of histone acetylation status to significantly improve DAT functional abnormalities, thereby identifying a novel and promising therapeutic target for OCD treatment.

Berberine has demonstrated an antidepressant-like effect in rodents. Moreover, it increases central 5-hydroxytryptamine (5-HT)/brain-derived neurotrophic factor (BDNF) or cyclic AMP response element binding protein (CREB) levels, but the exact role of these targets in its effect is still ill-explained. Therefore, the present study explored the role of 5-HT in berberine-induced antidepressant-like activity and BDNF or CREB expression in the specific brain regions. Administration of berberine (2, 5, and 20 mg/kg, i.p.) significantly reduced the duration of immobility of mice in the tail suspension test (TST) model without affecting locomotor activity, confirming its antidepressant-like potential. Preinjection with the 5-HT precursor, 5-hydroxytryptophan (5-HTP; 50 and 100 µg/mouse, intracerebroventricular [i.c.v.]), and the selective serotonin reuptake inhibitor (SSRI), fluoxetine (5 and 10 mg/kg, i.p.), enhanced the berberine-induced antidepressant-like effect, whereas it was reversed in mice pretreated with 5-HT_1A receptor agonist, 8-hydroxy-2(-dipropylamino)tetralinhydrobromide (8-OH-DPAT) (0.01 and 0.1 µg/mouse, i.c.v.), or the 5-HT_2A/2C receptor antagonist, mianserin (1, 1.5 µg/mouse, i.c.v.). Furthermore, berberine-induced antidepressant-like effects were significantly reduced in mice with depleted central 5-HT, achieved by preinjection of the serotonin depletor, p-chlorophenylalanine (p-CPA; 300 mg/kg, i.p. × 3 days). Additionally, berberine (20 mg/kg, i.p.) treatment significantly elevated BDNF expression in the whole brain, prefrontal cortex (PFC), and hippocampus and increased CREB expression in the whole brain and hippocampus only. Notably, berberine-induced elevated BDNF expression in the whole brain and hippocampus was further enhanced in mice pretreated with 5-HTP, fluoxetine, or 8-OH-DPAT, whereas mianserin or p-CPA reversed it. However, 5-HTP enhanced and fluoxetine or 8-OH-DPAT did not alter, whereas mianserin or p-CPA reversed the berberine-induced heightened BDNF expression in the PFC. On the other hand, berberine significantly increased CREB expression in the whole brain, which was further potentiated in mice pretreated with 5-HTP, fluoxetine, 8-OH-DPAT, or mianserin, whereas it was reversed by p-CPA. However, berberine-induced heightened CREB expression in the hippocampus was enhanced only in mice pretreated with 5-HTP and attenuated by preinjection of mianserin or p-CPA. These findings suggest that serotonergic transmission modulates the antidepressant-like activity and the BDNF/CREB alterations induced by berberine, likely through a mechanism mediated by 5-HT_1A and 5-HT_2A/2C receptors. This study underscores the role of serotonergic transmission in the effects induced by berberine.

Alzheimer's disease (AD) is characterized by the accumulation of tau tangles that aggregate into neurofibrillary tangles (NFT). This study aims to assess binding of [¹²⁵I]IPPI, a recently reported imaging probe for pathological, aggregated tau in AD human hippocampus (HP) postmortem brain slices, and measure effects of drugs known to bind to tau, monoamine oxidase A (MAO-A), and dual specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A). Quantitative [¹²⁵I]IPPI binding was compared between AD (n = 29; 13 male and 16 female) and cognitively normal (CN) (n = 32; 16 male and 16 female) subjects. Significantly, there was more [¹²⁵I]IPPI binding in AD gray matter (GM), which positively correlated with the percent of anti-tau immunostaining. GM/white matter (WM) ratios in AD were higher compared to CN subjects. Female AD (avg. GM/WM = 2.42) exhibited greater [¹²⁵I]IPPI binding compared to males (avg. GM/WM = 1.91). Binding of [¹²⁵I]IPPI increased with Braak neurofibrillary stages of the subjects, and the effects of aging were mixed, with females showing a downward trend. A positive correlation between [¹²⁵I]IPPI binding to tau and [¹⁸F]flotaza binding to amyloid beta (Aβ) suggests potential pathophysiological associations between the two AD biomarkers. MK-6240 (aggregated tau-selective) and harmine (MAO-A, DYRK1A, and tau nonselective) inhibited [¹²⁵I]IPPI binding by 88% and 69%, respectively. No effect on [¹²⁵I]IPPI binding was observed by selective DYRK1A (KuFal194) and MAO-A (clorgyline) inhibitors. Affinity of harmine for tau binding sites was quantified by inhibitor concentration (IC₅₀) = 135 ± 29 nM. This study demonstrates promise of radiolabeled IPPI as a viable and selective tau radiotracer to assist in the diagnostic imaging of AD in humans.

Objective: Migraines profoundly impact patients' quality of life. This study seeks to investigate the relationship between dysregulated miR-22-3p and the neuroinflammation and central sensitization associated with migraine.

Methods: Initially, the level of miR-22-3p in migraine patients were analyzed using RT-qPCR. Subsequently, a migraine model was established by administering nitroglycerin (NTG) to mice. To modulate the levels of miR-22-3p within this model, agomir was utilized. Following this intervention, mechanical and thermal pain sensitivity were evaluated by Von Frey filament and radiant heat. The levels of c-Fos, CGRP, TNF-α, IL-1β, and IL-6 in trigeminal nucleus caudalis (TNC) were detected by RT-qPCR and ELISA. Furthermore, dual luciferase reporting assays were conducted to ascertain whether miR-22-3p could target KLF6. Moreover, the influence of KLF6 on inflammatory cytokines and central sensitization were further studied.

Results: miR-22-3p was significantly reduced in migraine patients and NTG mice. In animals, overexpression of miR-22-3p significantly alleviated hyperalgesia and neuroinflammation induced by NTG. Following the overexpression of miR-22-3p, we observed an increase in thermal withdrawal latency, paw mechanical threshold, and periorbital mechanical threshold. Conversely, levels of c-Fos, CGRP, TNF-α, IL-1β, and IL-6 exhibited a significant reduction. We found that miR-22-3p can inhibit KLF6 expression. Additionally, further findings indicated that the suppression of KLF6 resulted in decreased pain sensitivity along with diminished expression of c-Fos, CGRP, TNF-α, IL-1β, and IL-6.

Conclusion: In the context of migraine, miR-22-3p may play a pivotal role in mitigating neuroinflammation and alleviating central sensitization through the inhibition of KLF6.