NeuropharmacologyPub Date : 2024-10-28DOI: 10.1016/j.neuropharm.2024.110200
Rui Wang , Li Zhu , Yunting Fan , Huiqing Du , Wei Han , Fanglin Guan , Yingjie Zhu , Tong Ni , Teng Chen
{"title":"Dopamine D3 receptor mediates natural and methamphetamine rewards via regulating the expression of miR-29c in the nucleus accumbens of mice","authors":"Rui Wang , Li Zhu , Yunting Fan , Huiqing Du , Wei Han , Fanglin Guan , Yingjie Zhu , Tong Ni , Teng Chen","doi":"10.1016/j.neuropharm.2024.110200","DOIUrl":"10.1016/j.neuropharm.2024.110200","url":null,"abstract":"<div><div>The dopamine D3 receptor (D3R), principally confined to the nucleus accumbens (NAc), is involved in regulating natural and drug rewards; however, the molecular mechanisms underlying the associated process remain unclear. Earlier research has reported the concurrent influence of D3R and miR-29c expressed in the NAc on methamphetamine (METH)-induced reward behaviors and microglial activation, hinting at regulatory roles in reward processing. Herein, we performed viral manipulation-mediating D3R/miR-29c overexpression and inhibition in the whole NAc in male D3R knockout and wild-type mice to investigate this potential relationship. Behavioral responses to the rewarding stimuli were assessed using sucrose preference score, METH-induced locomotor sensitization, and METH-induced conditioned place preference tests. Overall, we observed a notable decrease in the behavioral response to sucrose and METH in D3R-deficient mice, accompanied by the downregulation of miR-29c expression in the NAc. Diminished responses to those rewarding stimuli in D3R-deficient mice primarily stemmed from the reduction of GSK3β activity and subsequent down-regulation of miR-29c in the NAc. Microglial activation in the NAc mediates the effect of D3R-miR-29c deficiency on the reward effects of sucrose and METH. Pharmacological suppression of microglial activity rescued the reduced response in mice lacking D3R-miR-29c in the NAc. Overall, this study revealed the mechanism by which D3R regulates both natural and drug rewards via miR-29c in the murine NAc, highlighting the role of the NAc D3R-miR-29c pathway as a critical regulator of rewards, and providing new insights into the role of NAc D3R-miR-29c in encoding rewarding experiences.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110200"},"PeriodicalIF":4.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuropharmacologyPub Date : 2024-10-22DOI: 10.1016/j.neuropharm.2024.110199
Sorangely Vázquez Alicia, Félix G Rivera-Moctezuma, José L Marrero Valentín, Dinely Pérez, Eduardo L Tosado-Rodríguez, Abiel Roche Lima, Pedro A Ferchmin, Nadezhda Sabeva
{"title":"Neuroprotection by 4R-cembranoid against Gulf War Illness-related chemicals is mediated by ERK, PI3K, and CaMKII pathways.","authors":"Sorangely Vázquez Alicia, Félix G Rivera-Moctezuma, José L Marrero Valentín, Dinely Pérez, Eduardo L Tosado-Rodríguez, Abiel Roche Lima, Pedro A Ferchmin, Nadezhda Sabeva","doi":"10.1016/j.neuropharm.2024.110199","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2024.110199","url":null,"abstract":"<p><p>Gulf War Illness (GWI) has been consistently linked to exposure to pyridostigmine (PB), N,N-Diethyl-meta-toluamide (DEET), permethrin (PER), and traces of sarin. In this study, diisopropylfluorophosphate (DFP, sarin surrogate) and the GWI-related chemicals were found to reduce the number of functionally active neurons in rat hippocampal slices. These findings confirm a link between GWI neurotoxicants and N-Methyl-D-Aspartate (NMDA)-mediated excitotoxicity, which was successfully reversed by Edelfosine (a phospholipase Cβ (PLCβ3) inhibitor) and Flupirtine (a KCNQ/M (Kv7) channel agonist). To test whether 4R-cembranoid (4R), a nicotinic α7 acetylcholinesterase receptor (α7AChR) modulator known for its neuroprotective properties, can restore hippocampal neurons from glutamate-induced neurotoxicity, we exposed rat hippocampal slices with DFP for 10 min followed by 60 min treatment with 4R. We investigated the 4R mechanisms of neuroprotection after preincubation with LY294002, PD98059, and KN-62. The inhibition of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase kinase (MEK1/2), and calcium/calmodulin-dependent protein kinase (CaMKII) abrogated the protective effect of 4R against DFP-induced neurotoxicity. In separate experiments, after incubation with DFP, followed by 4R for 1 hr., cellular extracts were prepared for Western blotting of phospho-Akt, phospho-GSK3β, phosphorylated extracellular signal-regulated kinase (ERK)1/2, CaMKII and cAMP response element-binding protein (CREB). Our results show that DFP induces neuronal dysfunction by dephosphorylation, while 4R restores the phosphorylation of Akt, GSK3, ERK1/2, CREB, and CaMKII. Moreover, our proteomics analysis supported the notion that 4R activates additional signaling pathways related to enhancing neuronal signaling, synaptic plasticity, and apoptotic inhibition to promote cell survival against DFP, offering biomarkers for developing treatment against GWI.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110199"},"PeriodicalIF":4.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuropharmacologyPub Date : 2024-10-22DOI: 10.1016/j.neuropharm.2024.110196
Fernanda da Silva Rodrigues , Jeferson Jantsch , Gabriel de Farias Fraga , Victor Silva Dias , Camila Pereira Medeiros , Fernanda Wickert , Nadja Schroder , Marcia Giovernardi , Renata Padilha Guedes
{"title":"Cannabidiol partially rescues behavioral, neuroinflammatory and endocannabinoid dysfunctions stemming from maternal obesity in the adult offspring","authors":"Fernanda da Silva Rodrigues , Jeferson Jantsch , Gabriel de Farias Fraga , Victor Silva Dias , Camila Pereira Medeiros , Fernanda Wickert , Nadja Schroder , Marcia Giovernardi , Renata Padilha Guedes","doi":"10.1016/j.neuropharm.2024.110196","DOIUrl":"10.1016/j.neuropharm.2024.110196","url":null,"abstract":"<div><div>Maternal obesity is known to increase the risk of psychiatric disorders, such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While preventive measures are well-documented, practical approaches for addressing the damages once they are already established are limited. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on neuroinflammation and peripheral metabolic disturbances during adolescence, however, it is known that both factors tend to vary throughout life. Therefore, here we investigated the potential of CBD to mitigate these alterations in the adult offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) for 3 weeks from the 70th day of life. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and endocannabinoid markers were evaluated in the hypothalamus, prefrontal cortex (PFC) and hippocampus, as well as the biochemical profile in the plasma. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, restoring exacerbated astrocytic and microglial markers in the hypothalamus, PFC and hippocampus of the offspring, as well as endocannabinoid levels in the PFC, with notable sex differences. Additionally, CBD attenuated plasma glucose and lipopolysaccharides (LPS) concentrations in females. These findings underscore the persistent influence of maternal obesity on the offspring's health, encompassing metabolic irregularities and behavioral impairments, as well as the role of the endocannabinoid system in mediating these outcomes across the lifespan.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110196"},"PeriodicalIF":4.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuropharmacologyPub Date : 2024-10-21DOI: 10.1016/j.neuropharm.2024.110197
Régulo Olivares-García , Laura López-Cruz , Carla Carratalá-Ros , Paula Matas-Navarro , John D. Salamone , Mercè Correa
{"title":"Mild forced exercise in young mice prevents anergia induced by dopamine depletion in late adulthood: Relation to CDNF and DARPP-32 phosphorylation patterns in nucleus accumbens","authors":"Régulo Olivares-García , Laura López-Cruz , Carla Carratalá-Ros , Paula Matas-Navarro , John D. Salamone , Mercè Correa","doi":"10.1016/j.neuropharm.2024.110197","DOIUrl":"10.1016/j.neuropharm.2024.110197","url":null,"abstract":"<div><div>Mesolimbic dopamine (DA) plays a critical role in behavioral activation and exertion of effort in motivated behaviors. DA antagonism and depletion in nucleus accumbens (Nacb) induces anergia in effort-based decision-making tasks. Exercise improves motor function in Parkinson's disease (PD). However, the beneficial effects of physical exercise on anergia, a symptom present in many psychiatric and neurological pathologies needs to be studied. During 9 weeks, young CD1 male mice were trained to run at a moderate speed in automatically turning running wheels (RW) (forced exercise group) or locked in static RWs (control group) in 1 h daily sessions. Both groups were tested in a 3-choice-T-maze task developed for the assessment of preference between active (RW) vs. sedentary reinforcers, and vulnerability to DA depletion-induced anergia was studied after tetrabenazine administration (TBZ; VMAT-2 blocker). Exercise did not change spontaneous preferences, did not affect body weight, plasma corticosterone levels or measures of anxiety, but it increased the cerebral DA neurotrophic factor (CDNF) in Nacb core, suggesting a neuroprotective effect in this nucleus. After TBZ administration, only the non-trained group showed a shift in relative preferences from active to sedentary options, reducing time running but increasing consumption of pellets, thus showing a typical anergic but not anhedonic effect. Moreover, only in the non-trained group, phosphorylation of DARPP-32(Thr34) increased after TBZ administration. These results are the first to show that mild forced exercise carried out from a young age to adulthood could act on Nacb-related functions, and prevent the anergia-inducing effects of DA depletion.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110197"},"PeriodicalIF":4.6,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuropharmacologyPub Date : 2024-10-21DOI: 10.1016/j.neuropharm.2024.110198
Yan-Mei Chen , Jie Huang , Hua Fan , Wei-Yu Li , Tian-Shun Shi , Jie Zhao , Cheng-Niu Wang , Wei-Jia Chen , Bao-Lun Zhu , Jun-Jie Qian , Wei Guan , Bo Jiang
{"title":"QRFP and GPR103 in the paraventricular nucleus play a role in chronic stress-induced depressive-like symptomatology by enhancing the hypothalamic-pituitary-adrenal axis","authors":"Yan-Mei Chen , Jie Huang , Hua Fan , Wei-Yu Li , Tian-Shun Shi , Jie Zhao , Cheng-Niu Wang , Wei-Jia Chen , Bao-Lun Zhu , Jun-Jie Qian , Wei Guan , Bo Jiang","doi":"10.1016/j.neuropharm.2024.110198","DOIUrl":"10.1016/j.neuropharm.2024.110198","url":null,"abstract":"<div><div>Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for depression neurobiology. As the latest member of the RFamide peptide family in mammals, pyroglutamylated RFamide peptide (QRFP) is closely implicated in neuroendocrine maintenance by activating G-protein-coupled receptor 103 (GPR103). We hypothesized that QRFP and GPR103 might contribute to chronic stress-induced depression by promoting corticotropin-releasing hormone (CRH) release from neurons in the paraventricular nucleus (PVN), and various methods were employed in this study, with male C57BL/6J mice adopted as the experimental subjects. Chronic stress induced not only depression-like behaviors but also significant enhancement in QRFP and GPR103 in the PVN. Genetic overexpression of QRFP/GPR103 and stereotactic infusion of QRFP-26/QRFP-43 peptide in the PVN all mimicked chronic stress that induced various depression-like phenotypes in naïve mice, and this was mediated by promoting CRH biosynthesis and HPA activity. In contrast, genetic knockdown of QRFP/GPR103 in the PVN produced notable antidepressant-like effects in mice exposed to chronic stress. Furthermore, genetic knockout of QRFP also protected against chronic stress in mice. In addition, both the C-terminal biological region of QRFP and the downstream PKA/PKC-CREB signaling coupled to GPR103 stimulation underlie the role of QRFP and GPR103 in depression. Collectively, QRFP and GPR103 in PVN neurons could be viable targets for novel antidepressants.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110198"},"PeriodicalIF":4.6,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuropharmacologyPub Date : 2024-10-20DOI: 10.1016/j.neuropharm.2024.110195
Trevor T. Towner, Harper J. Coleman, Matthew A. Goyden, Andrew S. Vore, Kimberly M. Papastrat, Elena I. Varlinskaya, David F. Werner
{"title":"Prelimbic cortex perineuronal net expression and social behavior: Impact of adolescent intermittent ethanol exposure","authors":"Trevor T. Towner, Harper J. Coleman, Matthew A. Goyden, Andrew S. Vore, Kimberly M. Papastrat, Elena I. Varlinskaya, David F. Werner","doi":"10.1016/j.neuropharm.2024.110195","DOIUrl":"10.1016/j.neuropharm.2024.110195","url":null,"abstract":"<div><div>Adolescent intermittent ethanol (AIE) exposure in rats leads to social deficits. Parvalbumin (PV) expressing fast-spiking interneurons in the prelimbic cortex (PrL) contribute to social behavior, and perineuronal nets (PNNs) within the PrL preferentially encompass and regulate PV interneurons. AIE exposure increases PNNs, but it is unknown if this upregulation contributes to AIE-induced social impairments. The current study was designed to determine the effect of AIE exposure on PNN expression in the PrL and to assess whether PNN dysregulation contributes to social deficits elicited by AIE. cFos-LacZ male and female rats were exposed every other day to tap water or ethanol (4 g/kg, 25% w/v) via intragastric gavage between postnatal day (P) 25–45. We evaluated neuronal activation by β-galactosidase expression and PNN levels either at the end of the exposure regimen on P45 and/or in adulthood on P70. In addition, we used Chondroitinase ABC (ChABC) to deplete PNNs following adolescent exposure (P48) and allowed for PNN restoration before social testing in adulthhod. AIE exposure increased PNN expression in the PrL of adult males, but decreased PNNs immediately following AIE. Vesicular glutamate transporter 2 (vGlut2) and vesicular GABA transporter (vGat) near PNNs were downregulated only in AIE-exposed females. Gene expression of PNN components was largely unaffected by AIE exposure. Removal and reestablishment of PrL PNNs by ChABC led to upregulation of PNNs and social impairments in males, regardless of adolescent exposure. These data suggest that AIE exposure in males upregulates PrL PNNs that likely contribute to social impairments induced by AIE.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110195"},"PeriodicalIF":4.6,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuropharmacologyPub Date : 2024-10-16DOI: 10.1016/j.neuropharm.2024.110192
Hala Kawa , Zubair Ahmed , Arshad Majid , Ruoli Chen
{"title":"Inhibition of matrix metalloproteinases to reduce blood brain barrier disruption and haemorrhagic transformation in ischaemic stroke: Go broad or go narrow?","authors":"Hala Kawa , Zubair Ahmed , Arshad Majid , Ruoli Chen","doi":"10.1016/j.neuropharm.2024.110192","DOIUrl":"10.1016/j.neuropharm.2024.110192","url":null,"abstract":"<div><div>Ischaemic stroke characterises impulsive cerebral-region hypoxia due to deep intracerebral arteriole blockage, often accompanied by permanent cerebral infarction and cognitive impairment. Thrombolysis with recombinant tissue plasminogen activator (rtPA) and thrombectomy remain the only guidance-approved therapies. However, emerging data draws clear links between such therapies and haemorrhage transformation, which occur when cerebral vasculature is damaged during ischaemia/reperfusion. Studies have shown that matrix metalloproteinases (MMPs) play a significant role in haemorrhage transformation, by depleting the extracellular matrix (ECM) and disrupting the blood brain barrier (BBB). Inhibitors of MMPs may be used to prevent ischaemic stroke patients from BBB disruption and haemorrhage transformation, particularly for those receiving rtPA treatment. Preclinical studies found that inhibition of MMPs with agents or in knock out mice, effectively reduced BBB disruption and infarct volume, leading to improved ischaemic stroke outcomes. At present, MMP inhibition is not an approved therapy for stroke patients. There remain concerns about timing, dosing, duration of MMP inhibition and selection of either broad spectrum or specific MMP inhibitors for stroke patients. This review aims to summarize current knowledge on MMP inhibition in ischaemic stroke and explore whether a broad spectrum or a specific MMP inhibitor should be used for ischaemic stroke patient treatment. It is crucial to inhibit MMP activities early and sufficiently to ensure BBB intact during ischaemia and reperfusion, but also to reduce side effects of MMP inhibitors to minimum. Recent advance in stroke therapy by thrombectomy could aid in such treatment with intra-arterially delivery of MMP inhibitors (and/or antioxidants).</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110192"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuropharmacologyPub Date : 2024-10-16DOI: 10.1016/j.neuropharm.2024.110193
Teng He , Siqi Yang , Changmao Zhu , Bingyuan Zhang , Qi Zhang , Yawei Ji , Yuanyuan Wang , Riyue Jiang
{"title":"A bibliometric analysis of research on empathy for pain","authors":"Teng He , Siqi Yang , Changmao Zhu , Bingyuan Zhang , Qi Zhang , Yawei Ji , Yuanyuan Wang , Riyue Jiang","doi":"10.1016/j.neuropharm.2024.110193","DOIUrl":"10.1016/j.neuropharm.2024.110193","url":null,"abstract":"<div><div>Empathy for pain encompasses the processes of perceiving, understanding, and responding to the pain of others, playing a crucial role in social interaction and individual development. The increasing interest in this field has led to a surge in related publications; however, the overall quantity and quality of these works remain uncertain. To address this issue, we conducted a bibliometric analysis of research on empathy for pain. Our study meticulously examined 479 publications to provide a comprehensive analysis of bibliographic elements such as annual publication trends, authorship, country of origin, institutional affiliations, journals, and keywords. Our findings indicate that, although there has been a rise in research on empathy for pain in recent years, the volume remains insufficient and is predominantly concentrated in a few countries, authors, and institutions. Additionally, current research mainly focuses on four primary areas: perception, pain, empathy, and emotion. We assert that future research will likely explore the relationship between EEG measurements and empathy for pain to determine if such measurements can effectively quantify empathy, thereby enhancing clinical management.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110193"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuropharmacologyPub Date : 2024-10-16DOI: 10.1016/j.neuropharm.2024.110194
Gui-Feng Lu , Xin Yang , Zhi Xiao , Jia-Zhan Huang , Yi-Han Jiang , Meng-Qi Huang , Fei Geng
{"title":"Prefrontal TNRC6A mediates anxiety-like behaviour by regulating CRF through the maintenance of miR-21-3p stability","authors":"Gui-Feng Lu , Xin Yang , Zhi Xiao , Jia-Zhan Huang , Yi-Han Jiang , Meng-Qi Huang , Fei Geng","doi":"10.1016/j.neuropharm.2024.110194","DOIUrl":"10.1016/j.neuropharm.2024.110194","url":null,"abstract":"<div><div>Anxiety is an emotional response to a potential threat. It is characterized by worry, feelings of tension, and physical changes. Trinucleotide repeat containing adaptor 6A (TNRC6A) binds to argonaute (AGO) proteins and microRNAs to form the miRNA-induced silencing complex (miRISC), which mediates mRNA degradation, storage, and translational repression functions. However, whether TNRC6A is involved in anxiety regulation remains unknown.</div><div>In this study, TNRC6A was downregulated in the prefrontal cortex (PFC) of mice exposed to acute restraint stress. Inhibition of TNRC6A in PFC induced anxious behaviour. RNA immunoprecipitation, RNA pull-down and real-time quantitative PCR revealed that TNRC6A directly binds to miR-21-3p and maintains its stability. Intriguingly, miR-21-3p was downregulated in the PFC of acute stress mice, whereas overexpression of miR-21-3p significantly reduced anxiety-like behaviour. Furthermore, miR-21-3p knockdown significantly increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the PFC pyramidal neurons. Dual luciferase assay and western blotting confirmed that miR-21-3p binds to the 3 ‘UTR region of corticotropin-releasing factor (CRF) mRNA and regulates CRF and cAMP-response element binding protein (CREB) expression. These results confirm that low levels of TNRC6A in the PFC decrease the stability of miR-21-3p which promotes the up-regulation of CRF, leading to the development of anxiety-like behaviours. This research provides insight into a novel molecular mechanism by which TNRC6A regulates anxiety behaviour through the miR-21-3p/CRF signalling axis.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110194"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Glyphosate impairs both structure and function of GABAergic synapses in hippocampal neurons","authors":"Giuseppe Chiantia , Debora Comai , Enis Hidisoglu , Antonia Gurgone , Claudio Franchino , Valentina Carabelli , Andrea Marcantoni , Maurizio Giustetto","doi":"10.1016/j.neuropharm.2024.110183","DOIUrl":"10.1016/j.neuropharm.2024.110183","url":null,"abstract":"<div><div>Glyphosate (Gly) is a broad-spectrum herbicide responsible for the inhibition of the enzyme 5-enolpyruvylshikimate-3-phosphate synthase known to be expressed exclusively in plants and not in animals. For decades Gly has been thought to be ineffective in mammals, including humans, until it was demonstrated that rodents treated with the Gly-based herbicide Roundup showed reduced content of neurotransmitters (e.g., serotonin, dopamine, norepinephrine, and acetylcholine), increased oxidative stress in the brain associated with anxiety and depression-like behaviors and learning and memory deficits. Despite compelling evidence pointing to a neurotoxic effect of Gly, an in-depth functional description of its effects on synaptic transmission is still lacking. To investigate the synaptic alterations dependent on Gly administration we performed whole-cell patch-clamp recordings and immunocytochemistry on mouse primary cultured hippocampal neurons. Our findings reveal that 30 min incubation of Gly at the acceptable daily intake dose severely impaired inhibitory GABAergic synapses. Further analysis pointed out that Gly decreased the number of postsynaptic GABA<sub>A</sub> receptors and reduced the amplitude of evoked inhibitory postsynaptic currents, the readily releasable pool size available for synchronous release and the quantal size. Finally, a decreased number of release sites has been observed. Consistently, morphological analyses showed that the density of both pre- and post-synaptic inhibitory compartments decorating pyramidal cell dendrites was reduced by Gly. In conclusion, our experiments define for the first time the effects induced by Gly on GABAergic synapses, and reveal that Gly significantly impairs both pre- and postsynaptic mechanisms.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110183"},"PeriodicalIF":4.6,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}