Molecular Brain最新文献

{"title":"Synaptopodin is required for long-term depression at Schaffer collateral-CA1 synapses","authors":"Yanis Inglebert, Pei You Wu, Julia Tourbina-Kolomiets, Cong Loc Dang, R. Anne McKinney","doi":"10.1186/s13041-024-01089-3","DOIUrl":"https://doi.org/10.1186/s13041-024-01089-3","url":null,"abstract":"Synaptopodin (SP), an actin-associated protein found in telencephalic neurons, affects activity-dependant synaptic plasticity and dynamic changes of dendritic spines. While being required for long-term depression (LTD) mediated by metabotropic glutamate receptor (mGluR-LTD), little is known about its role in other forms of LTD induced by low frequency stimulation (LFS-LTD) or spike-timing dependent plasticity (STDP). Using electrophysiology in ex vivo hippocampal slices from SP-deficient mice (SPKO), we show that absence of SP is associated with a deficit of LTD at Sc-CA1 synapses induced by LFS-LTD and STDP. As LTD is known to require AMPA- receptors internalization and IP3-receptors calcium signaling, we tested by western blotting and immunochemistry if there were changes in their expression which we found to be reduced. While we were not able to induce LTD, long-term potentiation (LTP), albeit diminished in SPKO, can be recovered by using a stronger stimulation protocol. In SPKO we found no differences in NMDAR, which are the primary site of calcium signalling to induce LTP. Our study shows, for the first time, the key role of the requirement of SP to allow induction of activity-dependant LTD at Sc-CA1 synapses.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140562285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential contribution of canonical and noncanonical NLGN3 pathways to early social development and memory performance.","authors":"Lin-Yu Li, Ayako Imai, Hironori Izumi, Ran Inoue, Yumie Koshidaka, Keizo Takao, Hisashi Mori, Tomoyuki Yoshida","doi":"10.1186/s13041-024-01087-5","DOIUrl":"10.1186/s13041-024-01087-5","url":null,"abstract":"<p><p>Neuroligin (NLGN) 3 is a postsynaptic cell adhesion protein organizing synapse formation through two different types of transsynaptic interactions, canonical interaction with neurexins (NRXNs) and a recently identified noncanonical interaction with protein tyrosine phosphatase (PTP) δ. Although, NLGN3 gene is known as a risk gene for neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID), the pathogenic contribution of the canonical NLGN3-NRXN and noncanonical NLGN3-PTPδ pathways to these disorders remains elusive. In this study, we utilized Nlgn3 mutant mice selectively lacking the interaction with either NRXNs or PTPδ and investigated their social and memory performance. Neither Nlgn3 mutants showed any social cognitive deficiency in the social novelty recognition test. However, the Nlgn3 mutant mice lacking the PTPδ pathway exhibited significant decline in the social conditioned place preference (sCPP) at the juvenile stage, suggesting the involvement of the NLGN3-PTPδ pathway in the regulation of social motivation and reward. In terms of learning and memory, disrupting the canonical NRXN pathway attenuated contextual fear conditioning while disrupting the noncanonical NLGN3-PTPδ pathway enhanced it. Furthermore, disruption of the NLGN3-PTPδ pathway negatively affected the remote spatial reference memory in the Barnes maze test. These findings highlight the differential contributions of the canonical NLGN3-NRXN and noncanonical NLGN3-PTPδ synaptogenic pathways to the regulation of higher order brain functions associated with ASD and ID.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10935922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spermidine treatment: induction of autophagy but also apoptosis?","authors":"Maxinne Watchon, Amanda L Wright, Holly I Ahel, Katherine J Robinson, Stuart K Plenderleith, Andrea Kuriakose, Kristy C Yuan, Angela S Laird","doi":"10.1186/s13041-024-01085-7","DOIUrl":"10.1186/s13041-024-01085-7","url":null,"abstract":"<p><p>Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease that causes loss of balance and motor co-ordination, eventually leading to paralysis. It is caused by the autosomal dominant inheritance of a long CAG trinucleotide repeat sequence within the ATXN3 gene, encoding for an expanded polyglutamine (polyQ) repeat sequence within the ataxin-3 protein. Ataxin-3 containing an expanded polyQ repeat is known to be highly prone to intraneuronal aggregation, and previous studies have demonstrated that protein quality control pathways, such as autophagy, are impaired in MJD patients and animal models of the disease. In this study, we tested the therapeutic potential of spermidine on zebrafish and rodent models of MJD to determine its capacity to induce autophagy and improve functional output. Spermidine treatment of transgenic MJD zebrafish induced autophagy and resulted in increased distances swum by the MJD zebrafish. Interestingly, treatment of the CMVMJD135 mouse model of MJD with spermidine added to drinking water did not produce any improvement in motor behaviour assays, neurological testing or neuropathology. In fact, wild type mice treated with spermidine were found to have decreased rotarod performance when compared to control animals. Immunoblot analysis of protein lysates extracted from mouse cerebellar tissue found little differences between the groups, except for an increased level of phospho-ULK1 in spermidine treated animals, suggesting that autophagy was indeed induced. As we detected decreased motor performance in wild type mice following treatment with spermidine, we conducted follow up studies into the effects of spermidine treatment in zebrafish. Interestingly, we found that in addition to inducing autophagy, spermidine treatment also induced apoptosis, particularly in wild type zebrafish. These findings suggest that spermidine treatment may not be therapeutically beneficial for the treatment of MJD, and in fact warrants caution due to the potential negative side effects caused by induction of apoptosis.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10916058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutant α-synuclein causes death of human cortical neurons via ERK1/2 and JNK activation.","authors":"Hidefumi Suzuki, Naohiro Egawa, Keiko Imamura, Takayuki Kondo, Takako Enami, Kayoko Tsukita, Mika Suga, Yuichiro Yada, Ran Shibukawa, Ryosuke Takahashi, Haruhisa Inoue","doi":"10.1186/s13041-024-01086-6","DOIUrl":"10.1186/s13041-024-01086-6","url":null,"abstract":"<p><p>Synucleinopathies refer to a group of disorders characterized by SNCA/α-synuclein (α-Syn)-containing cytoplasmic inclusions and neuronal cell loss in the nervous system including the cortex, a common feature being cognitive impairment. Still, the molecular pathogenesis of cognitive decline remains poorly understood, hampering the development of effective treatments. Here, we generated induced pluripotent stem cells (iPSCs) derived from familial Parkinson's disease (PD) patients carrying SNCA A53T mutation, differentiating them into cortical neurons by a direct conversion method. Patient iPSCs-derived cortical neurons harboring mutant α-Syn exhibited increased α-Syn-positive aggregates, shorter neurites, and time-dependent vulnerability. Furthermore, RNA-sequencing analysis, followed by biochemical validation, identified the activation of the ERK1/2 and JNK cascades in cortical neurons with SNCA A53T mutation. This result was consistent with a reverted phenotype of neuronal death in cortical neurons when treated with ERK1/2 and JNK inhibitors, respectively. Our findings emphasize the role of ERK1/2 and JNK cascades in the vulnerability of cortical neurons in synucleinopathies, and they could pave the way toward therapeutic advancements for synucleinopathies.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10916047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crucial role of TFAP2B in the nervous system for regulating NREM sleep.","authors":"Ayaka Nakai, Mitsuaki Kashiwagi, Tomoyuki Fujiyama, Kanako Iwasaki, Arisa Hirano, Hiromasa Funato, Masashi Yanagisawa, Takeshi Sakurai, Yu Hayashi","doi":"10.1186/s13041-024-01084-8","DOIUrl":"10.1186/s13041-024-01084-8","url":null,"abstract":"<p><p>The AP-2 transcription factors are crucial for regulating sleep in both vertebrate and invertebrate animals. In mice, loss of function of the transcription factor AP-2β (TFAP2B) reduces non-rapid eye movement (NREM) sleep. When and where TFAP2B functions, however, is unclear. Here, we used the Cre-loxP system to generate mice in which Tfap2b was specifically deleted in the nervous system during development and mice in which neuronal Tfap2b was specifically deleted postnatally. Both types of mice exhibited reduced NREM sleep, but the nervous system-specific deletion of Tfap2b resulted in more severe sleep phenotypes accompanied by defective light entrainment of the circadian clock and stereotypic jumping behavior. These findings indicate that TFAP2B in postnatal neurons functions at least partly in sleep regulation and imply that TFAP2B also functions either at earlier stages or in additional cell types within the nervous system.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10900699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139983363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM2 improves microglia function and synaptic development in autism spectrum disorders by regulating P38 MAPK signaling pathway.","authors":"Yi Tian, Xiao Xiao, Weiliang Liu, Shanqing Cheng, Na Qian, Ling Wang, Yang Liu, Rong Ai, Xiaoping Zhu","doi":"10.1186/s13041-024-01081-x","DOIUrl":"10.1186/s13041-024-01081-x","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorder (ASD) encompasses a diverse range of neurodevelopmental disorders, but the precise underlying pathogenesis remains elusive. This study aim to explore the potential mechanism of TREM2 in regulating microglia function in ASD.</p><p><strong>Materials and methods: </strong>The offspring rat model of ASD was established through prenatal exposure to valproic acid (VPA), and the behavioral symptoms of the ASD model were observed. On postnatal day (PND) 7 and PND 28, the effects of prenatally exposure to VPA on synaptic development and microglia phenotype of offspring rats were observed. Primary microglia were cultured in vitro. Lentivirus and adenovirus were utilized to interfere with TREM2 and overexpress TREM2.</p><p><strong>Results: </strong>Prenatally VPA exposure induced offspring rats to show typical ASD core symptoms, which led to abnormal expression of synapse-related proteins in the prefrontal cortex of offspring rats, changed the phenotype of microglia in offspring rats, promoted the polarization of microglia to pro-inflammatory type, and increased inflammatory response. The experimental results in vitro showed that overexpression of TREM2 could increase the expression of Gephyrin, decrease the content of CD86 protein and increase the content of CD206 protein. In addition, after the expression of TREM2 was interfered, the content of p-P38 MAPK protein increased and the content of p-ELK-1 protein decreased.</p><p><strong>Conclusion: </strong>The protective influence of TREM2 on the VPA-induced ASD model is attributed to its inhibition of the P38 MAPK pathway, this protective effect may be achieved by promoting the polarization of microglia to anti-inflammatory phenotype and improving the neuronal synaptic development.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10898105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139972740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective enhancement of fear extinction by inhibiting neuronal adenylyl cyclase 1 (AC1) in aged mice.","authors":"Wantong Shi, Qi-Yu Chen, Yujie Ma, Jinjin Wan, Xu-Hui Li, Min Zhuo","doi":"10.1186/s13041-024-01083-9","DOIUrl":"10.1186/s13041-024-01083-9","url":null,"abstract":"<p><p>Adenylyl cyclase 1 (AC1) is a selective subtype of ACs, which is selectively expressed in neurons. The activation of AC1 is activity-dependent, and AC1 plays an important role in cortical excitation that contributes to chronic pain and related emotional disorders. Previous studies have reported that human-used NB001 (hNB001, a selective AC1 inhibitor) produced analgesic effects in different animal models of chronic pain. However, the potential effects of hNB001 on learning and memory have been less investigated. In the present study, we found that hNB001 affected neither the induction nor the expression of trace fear, but selectively enhanced the relearning ability during the extinction in aged mice. By contrast, the same application of hNB001 did not affect recent, remote auditory fear memory, or remote fear extinction in either adult or aged mice. Furthermore, a single or consecutive 30-day oral administration of hNB001 did not affect acute nociceptive response, motor function, or anxiety-like behavior in either adult or aged mice. Our results are consistent with previous findings that inhibition of AC1 did not affect general sensory, emotional, and motor functions in adult mice, and provide strong evidence that inhibiting the activity of AC1 may be beneficial for certain forms of learning and memory in aged mice.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10885434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139932060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A simple and reliable method for claustrum localization across age in mice.","authors":"Tarek Shaker, Gwyneth J Dagpa, Vanessa Cattaud, Brian A Marriott, Mariam Sultan, Mohammed Almokdad, Jesse Jackson","doi":"10.1186/s13041-024-01082-w","DOIUrl":"10.1186/s13041-024-01082-w","url":null,"abstract":"<p><p>The anatomical organization of the rodent claustrum remains obscure due to lack of clear borders that distinguish it from neighboring forebrain structures. Defining what constitutes the claustrum is imperative for elucidating its functions. Methods based on gene/protein expression or transgenic mice have been used to spatially outline the claustrum but often report incomplete labeling and/or lack of specificity during certain neurodevelopmental timepoints. To reliably identify claustrum projection cells in mice, we propose a simple immunolabelling method that juxtaposes the expression pattern of claustrum-enriched and cortical-enriched markers. We determined that claustrum cells immunoreactive for the claustrum-enriched markers Nurr1 and Nr2f2 are devoid of the cortical marker Tle4, which allowed us to differentiate the claustrum from adjoining cortical cells. Using retrograde tracing, we verified that nearly all claustrum projection neurons lack Tle4 but expressed Nurr1/Nr2f2 markers to different degrees. At neonatal stages between 7 and 21 days, claustrum projection neurons were identified by their Nurr1-postive/Tle4-negative expression profile, a time-period when other immunolabelling techniques used to localize the claustrum in adult mice are ineffective. Finally, exposure to environmental novelty enhanced the expression of the neuronal activation marker c-Fos in the claustrum region. Notably, c-Fos labeling was mainly restricted to Nurr1-positive cells and nearly absent from Tle4-positive cells, thus corroborating previous work reporting novelty-induced claustrum activation. Taken together, this method will aid in studying the claustrum during postnatal development and may improve histological and functional studies where other approaches are not amenable.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10874566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139898138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro modulation of mTOR and mGlur5 influence α-synuclein accumulation.","authors":"Viktoria Xing, Kyle Biggar, Stephen S G Ferguson, Shawn Hayley","doi":"10.1186/s13041-023-01074-2","DOIUrl":"10.1186/s13041-023-01074-2","url":null,"abstract":"<p><p>One of the main hallmarks of Parkinson's disease (PD) is abnormal alpha-synuclein (α-syn) aggregation which forms the main component of intracellular Lewy body inclusions. This short report used preformed α-syn fibrils, as well as an A53T mutant α-syn adenovirus to mimic conditions of pathological protein aggregation in dopaminergic human derived SH-SY5Y neural cells. Since there is evidence that the mTOR pathway and glutamatergic signaling each influence protein aggregation, we also assessed the impact of the mTOR inhibitor, rapamycin and the mGluR5 allosteric modulator, CTEP. We found that both rapamycin and CTEP induced a significant reduction of α-syn fibrils in SH-SY5Y cells and this effect was associated with a reduction in mTOR signaling and enhancement in autophagic pathway factors. These data support the possibility that CTEP (or rapamycin) might be a useful pharmacological approach to target abnormal α-syn accumulation by promoting intracellular degradation or enhanced clearance.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10870503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139741453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deleting IP6K1 stabilizes neuronal sodium-potassium pumps and suppresses excitability.","authors":"Hongfu Jin, Aili Liu, Alfred C Chin, Chenglai Fu, Hui Shen, Weiwei Cheng","doi":"10.1186/s13041-024-01080-y","DOIUrl":"10.1186/s13041-024-01080-y","url":null,"abstract":"<p><p>Inositol pyrophosphates are key signaling molecules that regulate diverse neurobiological processes. We previously reported that the inositol pyrophosphate 5-InsP₇, generated by inositol hexakisphosphate kinase 1 (IP6K1), governs the degradation of Na⁺/K⁺-ATPase (NKA) via an autoinhibitory domain of PI3K p85α. NKA is required for maintaining electrochemical gradients for proper neuronal firing. Here we characterized the electrophysiology of IP6K1 knockout (KO) neurons to further expand upon the functions of IP6K1-regulated control of NKA stability. We found that IP6K1 KO neurons have a lower frequency of action potentials and a specific deepening of the afterhyperpolarization phase. Our results demonstrate that deleting IP6K1 suppresses neuronal excitability, which is consistent with hyperpolarization due to an enrichment of NKA. Given that impaired NKA function contributes to the pathophysiology of various neurological diseases, including hyperexcitability in epilepsy, our findings may have therapeutic implications.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10863101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139730039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}