Progress in Neurobiology最新文献

{"title":"Caenorhabditis elegans RAC1/ced-10 mutants as a new animal model to study very early stages of Parkinson’s disease","authors":"A. Muñoz-Juan ,&nbsp;N. Benseny-Cases ,&nbsp;S. Guha ,&nbsp;I. Barba ,&nbsp;K.A. Caldwell ,&nbsp;G.A Caldwell ,&nbsp;L. Agulló ,&nbsp;V.J. Yuste ,&nbsp;A. Laromaine ,&nbsp;E. Dalfó","doi":"10.1016/j.pneurobio.2024.102572","DOIUrl":"10.1016/j.pneurobio.2024.102572","url":null,"abstract":"<div><p>Patients with Parkinson’s disease (PD) display non-motor symptoms arising prior to the appearance of motor signs and before a clear diagnosis. Motor and non-motor symptoms correlate with progressive deposition of the protein alpha-synuclein (Asyn) both within and outside of the central nervous system, and its accumulation parallels neurodegeneration. The genome of <em>Caenorhabditis elegans</em> does not encode a homolog of Asyn, thus rendering this nematode an invaluable system with which to investigate PD-related mechanisms in the absence of interference from endogenous Asyn aggregation. CED-10 is the nematode homolog of human RAC1, a small GTPase needed to maintain the function and survival of dopaminergic neurons against human Asyn-induced toxicity in <em>C. elegans</em>. Here, we introduce <em>C. elegans RAC1/ced-10</em> mutants as a predictive tool to investigate early PD symptoms before neurodegeneration occurs. Deep phenotyping of these animals reveals that, early in development, they displayed altered defecation cycles, GABAergic abnormalities and an increased oxidation index. Moreover, they exhibited altered lipid metabolism evidenced by the accumulation of lipid droplets. Lipidomic fingerprinting indicates that phosphatidylcholine and sphingomyelin, but not phosphatidylethanolamine or phosphatidylserine, were elevated in <em>RAC1/ced-10</em> mutant nematodes. These collective characteristics reflect the non-motor dysfunction, GABAergic neurotransmission defects, upregulation of stress response mechanisms, and metabolic changes associated with early-onset PD. Thus, we put forward an easy-to-manipulate preclinical animal model to deepen our understanding of early-stage PD and accelerate the translational path for therapeutic target discovery.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"234 ","pages":"Article 102572"},"PeriodicalIF":6.7,"publicationDate":"2024-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S030100822400008X/pdfft?md5=928a28aa42498e03b97b437f4c3cb18b&pid=1-s2.0-S030100822400008X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139508056","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}

{"title":"Barrel cortex development lacks a key stage of hyperconnectivity from deep to superficial layers in a rat model of Absence Epilepsy","authors":"Simona Plutino ,&nbsp;Emel Laghouati ,&nbsp;Guillaume Jarre ,&nbsp;Antoine Depaulis ,&nbsp;Isabelle Guillemain ,&nbsp;Ingrid Bureau","doi":"10.1016/j.pneurobio.2023.102564","DOIUrl":"10.1016/j.pneurobio.2023.102564","url":null,"abstract":"<div><p>During development of the sensory cortex, the ascending innervation from deep to upper layers provides a temporary scaffold for the construction of other circuits that remain at adulthood. Whether an alteration in this sequence leads to brain dysfunction in neuro-developmental diseases remains unknown. Using functional approaches in a genetic model of Absence Epilepsy (GAERS), we investigated in barrel cortex, the site of seizure initiation, the maturation of excitatory and inhibitory innervations onto layer 2/3 pyramidal neurons and cell organization into neuronal assemblies. We found that cortical development in GAERS lacks the early surge of connections originating from deep layers observed at the end of the second postnatal week in normal rats and the concomitant structuring into multiple assemblies. Later on, at seizure onset (1 month old), excitatory neurons are hyper-excitable in GAERS when compared to Wistar rats. These findings suggest that early defects in the development of connectivity could promote this typical epileptic feature and/or its comorbidities.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"234 ","pages":"Article 102564"},"PeriodicalIF":6.7,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S030100822300165X/pdfft?md5=2a870c7477d8d0ecd3792442846a43d0&pid=1-s2.0-S030100822300165X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139499613","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}

{"title":"Predictable navigation through spontaneous brain states with cognitive-map-like representations","authors":"Siyang Li ,&nbsp;Zhipeng Li ,&nbsp;Qiuyi Liu ,&nbsp;Peng Ren ,&nbsp;Lili Sun ,&nbsp;Zaixu Cui ,&nbsp;Xia Liang","doi":"10.1016/j.pneurobio.2024.102570","DOIUrl":"10.1016/j.pneurobio.2024.102570","url":null,"abstract":"<div><p>Just as navigating a physical environment, navigating through the landscapes of spontaneous brain states may also require an internal cognitive map. Contemporary computation theories propose modeling a cognitive map from a reinforcement learning perspective and argue that the map would be predictive in nature, representing each state as its upcoming states. Here, we used resting-state fMRI to test the hypothesis that the spaces of spontaneously reoccurring brain states are cognitive map-like, and may exhibit future-oriented predictivity. We identified two discrete brain states of the navigation-related brain networks during rest. By combining pattern similarity and dimensional reduction analysis, we embedded the occurrences of each brain state in a two-dimensional space. Successor representation modeling analysis recognized that these brain state occurrences exhibit place cell-like representations, akin to those observed in a physical space. Moreover, we observed predictive transitions of reoccurring brain states, which strongly covaried with individual cognitive and emotional assessments. Our findings offer a novel perspective on the cognitive significance of spontaneous brain activity and support the theory of cognitive map as a unifying framework for mental navigation.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"233 ","pages":"Article 102570"},"PeriodicalIF":6.7,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139469274","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":"Grid codes underlie multiple cognitive maps in the human brain","authors":"Dong Chen ,&nbsp;Nikolai Axmacher ,&nbsp;Liang Wang","doi":"10.1016/j.pneurobio.2024.102569","DOIUrl":"10.1016/j.pneurobio.2024.102569","url":null,"abstract":"<div><p>Grid cells fire at multiple positions that organize the vertices of equilateral triangles tiling a 2D space and are well studied in rodents. The last decade witnessed rapid progress in two other research lines on grid codes—empirical studies on distributed human grid-like representations in physical and multiple non-physical spaces, and cognitive computational models addressing the function of grid cells based on principles of efficient and predictive coding. Here, we review the progress in these fields and integrate these lines into a systematic organization. We also discuss the coordinate mechanisms of grid codes in the human entorhinal cortex and medial prefrontal cortex and their role in neurological and psychiatric diseases.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"233 ","pages":"Article 102569"},"PeriodicalIF":6.7,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139469587","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":"Tdrd3-null mice show post-transcriptional and behavioral impairments associated with neurogenesis and synaptic plasticity","authors":"Xingliang Zhu ,&nbsp;Yuyoung Joo ,&nbsp;Simone Bossi ,&nbsp;Ross A. McDevitt ,&nbsp;Aoji Xie ,&nbsp;Yue Wang ,&nbsp;Yutong Xue ,&nbsp;Shuaikun Su ,&nbsp;Seung Kyu Lee ,&nbsp;Nirnath Sah ,&nbsp;Shiliang Zhang ,&nbsp;Rong Ye ,&nbsp;Alejandro Pinto ,&nbsp;Yongqing Zhang ,&nbsp;Kimi Araki ,&nbsp;Masatake Araki ,&nbsp;Marisela Morales ,&nbsp;Mark P. Mattson ,&nbsp;Henriette van Praag ,&nbsp;Weidong Wang","doi":"10.1016/j.pneurobio.2024.102568","DOIUrl":"10.1016/j.pneurobio.2024.102568","url":null,"abstract":"<div><p>The <u>Top</u>oisomerase <u>3B</u> (Top3b) - <u>T</u>u<u>d</u>o<u>r d</u>omain containing <u>3</u><span> (Tdrd3) protein complex is the only dual-activity topoisomerase complex that can alter both DNA and RNA topology in animals. </span><em>TOP3B</em><span> mutations in humans are associated with schizophrenia<span><span>, autism and </span>cognitive disorders; and </span></span><em>Top3b</em><span>-null mice exhibit several phenotypes observed in animal models of psychiatric and cognitive disorders, including impaired cognitive and emotional behaviors<span>, aberrant neurogenesis<span> and synaptic plasticity, and transcriptional defects. Similarly, human </span></span></span><em>TDRD3</em> genomic variants have been associated with schizophrenia, verbal short-term memory and educational attainment. However, the importance of <em>Tdrd3</em> in normal brain function has not been examined in animal models. Here we generated a <em>Tdrd3</em>-null mouse strain and demonstrate that these mice display both shared and unique defects when compared to <em>Top3b-</em>null mice. Shared defects were observed in cognitive behaviors, synaptic plasticity, adult neurogenesis, newborn neuron morphology, and neuronal activity-dependent transcription; whereas defects unique to <em>Tdrd3</em><span><span>-deficient mice include hyperactivity, changes in anxiety-like behaviors, olfaction<span>, increased new neuron complexity, and reduced myelination. Interestingly, multiple genes critical for </span></span>neurodevelopment and cognitive function exhibit reduced levels in mature but not nascent transcripts. We infer that the entire Top3b-Tdrd3 complex is essential for normal brain function, and that defective post-transcriptional regulation could contribute to cognitive and psychiatric disorders.</span></p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"233 ","pages":"Article 102568"},"PeriodicalIF":6.7,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139422235","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":"Dissecting neural circuits from rostral ventromedial medulla to spinal trigeminal nucleus bidirectionally modulating craniofacial mechanical sensitivity","authors":"Yang Xue,&nbsp;Siyi Mo,&nbsp;Yuan Li,&nbsp;Ye Cao,&nbsp;Xiaoxiang Xu,&nbsp;Qiufei Xie","doi":"10.1016/j.pneurobio.2023.102561","DOIUrl":"10.1016/j.pneurobio.2023.102561","url":null,"abstract":"<div><p><span><span><span>Chronic craniofacial pain is intractable and its mechanisms remain unclarified. The rostral ventromedial medulla (RVM) plays a crucial role in descending pain facilitation and inhibition. It is unclear how the descending circuits from the RVM to </span>spinal trigeminal nucleus (Sp5) are organized to bidirectionally modulate craniofacial </span>nociception. We used viral tracing, </span><em>in vivo</em><span><span> optogenetics, </span>calcium signaling<span> recording, and chemogenetic manipulations to investigate the structure and function of RVM-Sp5 circuits. We found that most RVM neurons projecting to Sp5 were GABAergic or glutamatergic and facilitated or inhibited craniofacial nociception, respectively. Both GABAergic interneurons<span> and glutamatergic projection neurons in Sp5 received RVM inputs: the former were antinociceptive, whereas the latter were pronociceptive. Furthermore, we demonstrated activation of both GABAergic and glutamatergic Sp5 neurons receiving RVM inputs in inflammation- or dysfunction-induced masseter hyperalgesia. Activating GABAergic Sp5 neurons or inhibiting glutamatergic Sp5 neurons that receive RVM projections reversed masseter hyperalgesia. Our study identifies specific cell types and projections of RVM-Sp5 circuits involved in facilitating or inhibiting craniofacial nociception respectively. Selective manipulation of RVM-Sp5 circuits can be used as potential treatment strategy to relieve chronic craniofacial muscle pain.</span></span></span></p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"232 ","pages":"Article 102561"},"PeriodicalIF":6.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139015281","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":"ABHD6 drives endocytosis of AMPA receptors to regulate synaptic plasticity and learning flexibility","authors":"Mengping Wei ,&nbsp;Lei Yang ,&nbsp;Feng Su ,&nbsp;Ying Liu ,&nbsp;Xinyi Zhao ,&nbsp;Lin Luo ,&nbsp;Xinyue Sun ,&nbsp;Sen Liu ,&nbsp;Zhaoqi Dong ,&nbsp;Yong Zhang ,&nbsp;Yun Stone Shi ,&nbsp;Jing Liang ,&nbsp;Chen Zhang","doi":"10.1016/j.pneurobio.2023.102559","DOIUrl":"10.1016/j.pneurobio.2023.102559","url":null,"abstract":"<div><p><span>Trafficking of α‐Amino‐3–hydroxy‐5–methylisoxazole‐4–propionic acid (AMPA) receptors (AMPARs), mediated by AMPAR<span> interacting proteins, enabled neurons to maintain tuning capabilities at rest or active state. α/β-Hydrolase domain-containing 6 (ABHD6), an endocannabinoid<span> hydrolase, was an AMPAR auxiliary subunit found to negatively regulate the surface delivery of AMPARs. While ABHD6 was found to prevent AMPAR tetramerization in endoplasmic reticulum, ABHD6 was also reported to localize at postsynaptic site. Yet, the role of ABHD6 interacting with AMPAR at postsynaptic site, and the physiological significance of ABHD6 regulating AMPAR trafficking remains elusive. Here, we generated the ABHD6 knockout (ABHD6</span></span></span>^KO<span><span>) mice and found that deletion of ABHD6 selectively enhanced AMPAR-mediated basal synaptic responses and the surface expression of postsynaptic AMPARs. Furthermore, we found that loss of ABHD6 impaired hippocampal long-term depression (LTD) and synaptic downscaling in hippocampal synapses. AMPAR internalization assays revealed that ABHD6 was essential for neuronal activity-dependent </span>endocytosis of surface AMPARs, which is independent of ABHD6's hydrolase activity. The defects of AMPAR endocytosis and LTD are expressed as deficits in learning flexibility in ABHD6</span>^KO mice. Collectively, we demonstrated that ABHD6 is an endocytic accessory protein promoting AMPAR endocytosis, thereby contributes to the formation of LTD, synaptic downscaling and reversal learning.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"233 ","pages":"Article 102559"},"PeriodicalIF":6.7,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139070476","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":"Phase of neural oscillations as a reference frame for attention-based routing in visual cortex","authors":"Ehsan Aboutorabi ,&nbsp;Sonia Baloni Ray ,&nbsp;Daniel Kaping ,&nbsp;Farhad Shahbazi ,&nbsp;Stefan Treue ,&nbsp;Moein Esghaei","doi":"10.1016/j.pneurobio.2023.102563","DOIUrl":"10.1016/j.pneurobio.2023.102563","url":null,"abstract":"<div><p>Selective attention allows the brain to efficiently process the image projected onto the retina, selectively focusing neural processing resources on behaviorally relevant visual information. While previous studies have documented the crucial role of the action potential rate of single neurons in relaying such information, little is known about how the activity of single neurons relative to their neighboring network contributes to the efficient representation of attended stimuli and transmission of this information to downstream areas. Here, we show in the dorsal visual pathway of monkeys (medial superior temporal area) that neurons fire spikes preferentially at a specific phase of the ongoing population beta (∼20 Hz) oscillations of the surrounding local network. This preferred spiking phase shifts towards a later phase when monkeys selectively attend towards (rather than away from) the receptive field of the neuron. This shift of the locking phase is positively correlated with the speed at which animals report a visual change. Furthermore, our computational modeling suggests that neural networks can manipulate the preferred phase of coupling by imposing differential synaptic delays on postsynaptic potentials. This distinction between the locking phase of neurons activated by the spatially attended stimulus vs. that of neurons activated by the unattended stimulus, may enable the neural system to discriminate relevant from irrelevant sensory inputs and consequently filter out distracting stimuli information by aligning the spikes which convey relevant/irrelevant information to distinct phases linked to periods of better/worse perceptual sensitivity for higher cortices. This strategy may be used to reserve the narrow windows of highest perceptual efficacy to the processing of the most behaviorally relevant information, ensuring highly efficient responses to attended sensory events.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"233 ","pages":"Article 102563"},"PeriodicalIF":6.7,"publicationDate":"2023-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301008223001648/pdfft?md5=f287bf2456194346458c7bb8762f746c&pid=1-s2.0-S0301008223001648-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139032518","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}

{"title":"Traumatic brain injury derived pathological tau polymorphs induce the distinct propagation pattern and neuroinflammatory response in wild type mice","authors":"Nicha Puangmalai ,&nbsp;Nemil Bhatt ,&nbsp;Alice Bittar ,&nbsp;Cynthia Jerez ,&nbsp;Nikita Shchankin ,&nbsp;Rakez Kayed","doi":"10.1016/j.pneurobio.2023.102562","DOIUrl":"10.1016/j.pneurobio.2023.102562","url":null,"abstract":"<div><p>The misfolding and aggregation of the tau protein into neurofibrillary tangles constitutes a central feature of tauopathies. Traumatic brain injury (TBI) has emerged as a potential risk factor, triggering the onset and progression of tauopathies. Our previous research revealed distinct polymorphisms in soluble tau oligomers originating from single versus repetitive mild TBIs. However, the mechanisms orchestrating the dissemination of TBI brain-derived tau polymorphs (TBI-BDTPs) remain elusive. In this study, we explored whether TBI-BDTPs could initiate pathological tau formation, leading to distinct pathogenic trajectories. Wild-type mice were exposed to TBI-BDTPs from sham, single-blast (SB), or repeated-blast (RB) conditions, and their memory function was assessed through behavioral assays at 2- and 8-month post-injection. Our findings revealed that RB-BDTPs induced cognitive and motor deficits, concurrently fostering the emergence of toxic tau aggregates within the injected hippocampus. Strikingly, this tau pathology propagated to cortical layers, intensifying over time. Importantly, RB-BDTP-exposed animals displayed heightened glial cell activation, NLRP3 inflammasome formation, and increased TBI biomarkers, particularly triggering the aggregation of S100B, which is indicative of a neuroinflammatory response. Collectively, our results shed light on the intricate mechanisms underlying TBI-BDTP-induced tau pathology and its association with neuroinflammatory processes. This investigation enhances our understanding of tauopathies and their interplay with neurodegenerative and inflammatory pathways following traumatic brain injury.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"232 ","pages":"Article 102562"},"PeriodicalIF":6.7,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301008223001636/pdfft?md5=b077c73ebac19a0192fc620dcc67a4f0&pid=1-s2.0-S0301008223001636-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138885982","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}

{"title":"FAME4-associating YEATS2 knockdown impairs dopaminergic synaptic integrity and leads to seizure-like behaviours in Drosophila melanogaster","authors":"Luca Lo Piccolo ,&nbsp;Ranchana Yeewa ,&nbsp;Sureena Pohsa ,&nbsp;Titaree Yamsri ,&nbsp;Daniel Calovi ,&nbsp;Jutarop Phetcharaburanin ,&nbsp;Manida Suksawat ,&nbsp;Thanaporn Kulthawatsiri ,&nbsp;Vorasuk Shotelersuk ,&nbsp;Salinee Jantrapirom","doi":"10.1016/j.pneurobio.2023.102558","DOIUrl":"10.1016/j.pneurobio.2023.102558","url":null,"abstract":"<div><p><span>Familial adult myoclonus epilepsy (FAME) is a neurological disorder caused by a </span><em>TTTTA/TTTCA</em> intronic repeat expansion. FAME4 is one of the six types of FAME that results from the repeat expansion in the first intron of the gene <em>YEATS2</em>. Although the RNA toxicity is believed to be the primary mechanism underlying FAME, the role of genes where repeat expansions reside is still unclear, particularly in the case of YEATS2 in neurons. This study used <em>Drosophila</em> to explore the effects of reducing <em>YEATS2</em> expression. Two pan-neuronally driven <em>dsDNA</em> were used for knockdown of <em>Drosophila YEATS2</em> (<em>dYEATS2</em>), and the resulting molecular and behavioural outcomes were evaluated. <em>Drosophila</em> with reduced <em>dYEATS2</em> expression exhibited decreased tolerance to acute stress, disturbed locomotion, abnormal social behaviour, and decreased motivated activity. Additionally, reducing <em>dYEATS2</em> expression negatively affected <span><em>tyrosine hydroxylase</em></span> (<em>TH</em><span>) gene expression, resulting in decreased dopamine biosynthesis. Remarkably, seizure-like behaviours induced by knocking down </span><em>dYEATS2</em><span> were rescued by the administration of L-DOPA. This study reveals a novel role of YEATS2 in neurons in regulating acute stress responses, locomotion, and complex behaviours, and suggests that haploinsufficiency of YEATS2 may play a role in FAME4.</span></p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"233 ","pages":"Article 102558"},"PeriodicalIF":6.7,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138821059","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}