American journal of physiology. Cell physiology最新文献

{"title":"Transmission of Peripheral-blood α-Synuclein Fibrils Exacerbates Synucleinopathy and Neurodegeneration in Parkinson's Disease by Endothelial Lag3 Endocytosis.","authors":"Qingrui Duan, Qingxi Zhang, ShuoLin Jiang, Kun Nie, Shujun Feng, Yihui Qiu, Peikun He, Yuxuan Xing, Jiaxuan Liu, Guixian Ma, Yuhu Zhang, Yuyuan Gao, Lijuan Wang","doi":"10.1152/ajpcell.00639.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00639.2024","url":null,"abstract":"<p><p><b>Background:</b> Parkinson's disease (PD) is an age-related neurodegenerative disorder. The pathological feature of PD is abnormal alpha-synuclein (α-syn) formation and transmission. Recent evidence demonstrates that α-syn preformed fibrils (α-syn PFF) can be detected in the serum of PD patients. The peripheral-blood α-syn PFF can cross the blood-brain barrier and aggravate neuronal damage, but the mechanism remains to be elucidated. <b>Methods:</b> We constructed the PD mouse models of different severity: the mild pathology (A53T ONLY) and the severe pathology (A53T+Brain FIB); this was followed by α-syn PFFs intravenous injection. Then, we used endothelium-specific Lag3 knockout mice (Lag3-ECs-CKO) to decrease the blood α-syn PFFs spreading. <b>Results:</b> We observed that intravenous transmission of α-syn PFFs significantly aggravated motor deficits, dopaminergic neuron loss, neuroinflammation and pathologic α-syn deposition in A53T ONLY, but not in A53T+Brain FIB. Blocking endothelial Lag3 endocytosis by Lag3-ECs-CKO decreased the blood α-syn PFFs spreading and improved the symptoms and pathogenesis of PD mice. <b>Conclusions:</b> Our findings reveal the role of peripheral-blood α-syn PFFs transmission in the mild pathology or early-stage PD and the mechanism of endothelial Lag3 endocytosis in the pathology of α-syn transmission. Targeting endothelial Lag3 to prevent α-syn from spreading from the blood to the brain may be a disease-modifying therapy in early-stage PD.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Focal adhesions, reticular adhesions, flat clathrin lattices: What divides them, what unites them?","authors":"Fabian Lukas, Marlen Duchmann, Tanja Maritzen","doi":"10.1152/ajpcell.00821.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00821.2024","url":null,"abstract":"<p><p>The majority of cells within multicellular organisms requires anchorage to their surroundings in the form of cell-cell or cell-matrix adhesions. In regards to cell-matrix adhesions the transmembrane receptors of the integrin family have long been recognized as the central scaffold around which these adhesion complexes are built. Via their extracellular domains integrins bind extracellular matrix ligands while their intracellular tails interact with a plethora of proteins that link integrin-based adhesions to the cytoskeleton and turn them also into important signaling platforms. Depending on the specific intracellular interactome of the integrins, different types of integrin adhesion complexes have been classified. The best studied ones are the focal adhesions in which integrins become firmly linked to contractile actomyosin fibers allowing for force transduction. But integrins also form an integral part of adhesion structures that lack the strong actomyosin link and are enriched in endocytic proteins. These have been named reticular adhesions, flat clathrin lattices or clathrin plaques. Initially, the different types of integrin adhesion complexes have been viewed as discrete entities with their own separate life cycles. However, in the past years it has become more and more apparent how closely intertwined they are. In fact, it was shown that they can trigger each other´s biogenesis or can even directly convert into each other. Here, we will describe similarities as well as differences between integrin adhesion complexes focusing on the versatile αvß5 integrins and discuss the recently discovered close links and interconversion modes between the different αvß5 integrin adhesion types.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anxio-d epressive phenotype and impaired memory in mice with a conditional knockout of brain-derived neurotrophic factor in endothelial cells.","authors":"Aurore Quirié, Damien Mor, Alexandre Méloux, Adeline Etievant, Philippe Garnier, Perle Totoson, Julien Wirtz, Anne Prigent-Tessier, Christine Marie, Céline Demougeot","doi":"10.1152/ajpcell.00699.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00699.2024","url":null,"abstract":"<p><p>The present study investigated the role of endothelial BDNF in cognition. Male adult mice with a selective knockout of BDNF in endothelial cells (<i>BDNF^ECKO</i>) and their wild-type littermates (WT) were subjected to tests for detection of anxiety- and depression-like behaviors and impaired recognition memory. Neuronal activity and synaptogenesis were assessed from hippocampal levels of c-fos and synaptophysin, respectively, and cerebral capillary density from forebrain levels of CD31. BDNF/TrkB (tropomyosin-related kinase type B) receptor signaling was investigated through hippocampal levels of BDNF and activated TrkB receptors coupled with their immunolabelling by neurons and endothelial cells from both cerebrovascular fractions enriched in capillaries and hippocampal arterioles. Endothelial nitric oxide (NO) production was assessed from expression of endothelial NO synthase phosphorylated at serine 1177. <i>BDNF^ECKO</i> mice exhibited anxio-depressive phenotype, impaired memory and reduced synaptogenesis. Neither neuronal activity, neuronal BDNF/TrkB signaling nor capillary density differed between <i>BDNF^ECKO</i> and WT mice. However, endothelial-activated TrkB receptors as well as endothelial NO production and hippocampal BDNF levels were lower in <i>BDNF^ECKO</i> than WT mice. We conclude that endothelial BDNF is involved in cognition through mechanisms independent of neuronal BDNF/TrkB signaling and that endothelial NO might be a driver of the pro-cognitive effect of endothelial BDNF.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Placental extracellular vesicles from severe preeclamptic women alter calcium homeostasis in cardiomyocytes: An <i>ex vivo</i> study.","authors":"Saravanakumar Murugesan, Lakshmi Saravanakumar, Sakthivel Sadayappan, Ramaswamy Kannappan, Rachel G Sinkey, Michelle D Tubinis, Alan N Tita, Tamas Jilling, Dan E Berkowitz","doi":"10.1152/ajpcell.00409.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00409.2024","url":null,"abstract":"<p><p>Women with severe preeclampsia (sPE) exhibit a heightened risk of postpartum cardiovascular disease compared to those with normotensive pregnancies (NTP). While placental extracellular vesicles (EV) play a crucial role in feto-maternal communication, their impact on cardiomyocytes, particularly in the context of sPE, remains unclear. This study investigated the effect of sPE-associated placental EV (sPE-Plex EV) on cardiomyocyte calcium dynamics. We hypothesized that sPE-Plex EV mediates cardiomyocyte dysfunction by disrupting calcium signaling. EV were isolated from plasma and placental explant culture (Plex) using precipitation methods, and confirmed as Plex EV by PLAP activity and electron microscopy. Moreover, confocal microscopy confirmed the uptake of plasma EV in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and Plex EV by human AC-16 cardiomyocytes (hAC-16CM) cells. hiPSC-CM cells treated with sPE-EV and hAC-16CM cells treated with sPE-Plex EV exhibited significantly lower levels of Stromal interaction molecule 1 (STIM1) and Phospholamban (PLN) proteins compared to those treated with normotensive controls EV, as confirmed by western blot analysis. Treatment with sPE-Plex EV also resulted in the downregulation of STIM1 and PLN proteins in murine cardiomyocyte (mCM) cells compared to treatment with NTP-Plex EV. Our findings suggest that both plasma EV and Plex EV from sPE may alter calcium signaling in cardiac cells by downregulating calcium sensor proteins (STIM1 and PLN). Therefore, plasma EV and Plex EV from sPE pregnancies have adverse effects by altering calcium dynamics in hiPSC-CM, hAC-16CM, and mCM compared to normotensive control and potential impairment of cardiomyocyte function <i>ex vivo</i>.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In vitro</i> Examination of Piezo1-TRPV4 Dynamics: Implications for Placental Endothelial Function in Normal and Preeclamptic Pregnancies.","authors":"Hanna H Allerkamp, Alexander I Bondarenko, Ines Tawfik, Nilüfer Kamali-Simsek, Monika Horvat Mercnik, Corina T Madreiter-Sokolowski, Christian Wadsack","doi":"10.1152/ajpcell.00794.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00794.2024","url":null,"abstract":"<p><p>Mechanosensation is essential for endothelial cell (EC) function, which is compromised in early-onset preeclampsia (EPE), impacting offspring health. The ion channels Piezo-type mechanosensitive ion channel component 1 (Piezo1) and Transient receptor potential cation channel subfamily V member 4 (TRPV4) are co-regulated mechanosensors in ECs. Current evidence suggests that both channels could mediate aberrant placental endothelial function in EPE. Using isolated feto-placental ECs (fpECs) from early control (EC) and EPE pregnancies, we show functional co-expression of both channels and that Ca²⁺ influx and membrane depolarization in response to chemical channel activation is reduced in EPE fpECs. Downstream of channel activation, Piezo1 alone can induce phosphorylation of endothelial nitric oxide synthase (eNOS) in fpECs, while combined activation of Piezo1 and TRPV4 only affects eNOS phosphorylation in EPE fpECs. Additionally, combined activation reduces the barrier integrity of fpECs, also with a stronger effect on EPE fpECs. This implies altered Piezo1-TRPV4 co-regulation in EPE. Mechanistically, we suggest this to be driven by changes in the arachidonic acid metabolism in EPE fpECs as identified by RNA-Seq. Targeting of Piezo1 and TRPV4 might hold potential for EPE treatment options in the future.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diversity in Chemotherapy-Induced Cachexia.","authors":"Leah J Novinger, Natalia M Weinzierl, Andrea Bonetto","doi":"10.1152/ajpcell.00773.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00773.2024","url":null,"abstract":"<p><p>Preclinical and clinical studies suggest that chronic administration of cytotoxic drugs (<i>e.g.</i>, chemotherapy) may contribute to the occurrence of skeletal muscle wasting and weakness/fatigue (<i>i.e.</i>, cachexia). Doxorubicin, folfiri, and cisplatin are known to promote cachexia by triggering common alterations such as skeletal muscle atrophy, protein breakdown, and mitochondrial dysfunction, whereas each also possesses distinguishing features in terms of the activated molecular pathways. Similarly, commonalities exist between different cancer types including the development of muscle wasting early in treatment that can persist for years. The impact of treatment for gastrointestinal, head and neck and non-small cell lung cancers on the development of cachexia and survival outcomes is well documented. However, a disconnect occurs between preclinical studies on cachexia, which are often performed on younger mice, and clinical studies on cachexia, which are focused on patients over 60 years old. Yet, several preclinical studies have examined the impact of age on chemotherapy-induced cachexia. Finally, sex differences have been identified in both preclinical and clinical studies focused on the onset of cachexia consequential to chemotherapy administration and raise the question of whether treatments for this condition should be based on sex specificities. In conclusion, while cancer cachexia has been widely studied for its impact on patients affected by various malignancies, the effects of chemotherapy on the development of cachexia are less explored. Here, we examine diversity in chemotherapy-induced cachexia with respect to specific types of chemotherapy regimens and cancer, as well as differences based on age and sex.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STIM1 and lipid interactions at ER-PM contact sites.","authors":"Yuepeng Ke, Ritchel Gannaban, Junchen Liu, Yubin Zhou","doi":"10.1152/ajpcell.00634.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00634.2024","url":null,"abstract":"<p><p>Store-operated calcium (Ca²⁺) entry (SOCE) represents a major route of Ca²⁺ permeation across the plasma membrane (PM) in non-excitable cells, which plays an indispensable role in maintaining intracellular Ca²⁺ homeostasis. This process is orchestrated through the dynamic coupling between the endoplasmic reticulum (ER)-localized Ca²⁺ sensor stromal interaction molecule 1 (STIM1) and the PM-resident ORAI1 channel. Upon depletion of ER Ca²⁺ stores, STIM1 undergoes conformational rearrangements and oligomerization, leading to translocation of STIM1-containing ER membrane towards the PM. This movement is facilitated by the physical interaction between positively charged cytosolic domains within STIM1 and negatively charged phospholipids embedded in the PM, ultimately enabling its binding to and activation of the PM-embedded ORAI1 channel. In this mini-review, we provide an overview of STIM1-mediated Ca²⁺ signaling at ER-PM contact sites, highlighting the regulatory roles of phospholipids in the inner leaflet and sphingolipids in the outer leaflet of the PM. We also discuss the development of molecular tools that enable real-time visualization and manipulation of membrane contact sites (MCSs) at ER-PM junctions. Lastly, we highlight recent progress in developing targeted therapies for human diseases linked to STIM1 mutations and dysregulated Ca²⁺ signaling at ER-PM MCSs.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Animal models of haploinsufficiency revealed the isoform-specific role of GSK-3 in HFD-induced obesity and glucose intolerance.","authors":"Manisha Gupte, Prachi Umbarkar, Jacob Lemon, Sultan Tousif, Hind Lal","doi":"10.1152/ajpcell.00552.2024","DOIUrl":"10.1152/ajpcell.00552.2024","url":null,"abstract":"<p><p>Glycogen synthase kinase 3 (GSK-3), a serine-threonine kinase with two isoforms (α and β) is implicated in the pathogenesis of type 2 diabetes mellitus (T2D). Recently, we reported the isoform-specific role of GSK-3 in T2D using homozygous GSK-3α/β knockout mice. Although the homozygous inhibition models are idealistic in a preclinical setting, they do not mimic the inhibition seen with pharmacological agents. Hence, in this study, we sought to investigate the dose-response effect of GSK-3α/β inhibition in the pathogenesis of obesity-induced T2D. Specifically, to gain insight into the dose-response effect of GSK-3 isoforms in T2D, we generated tamoxifen-inducible global GSK-3α/β heterozygous mice. GSK-3α/β heterozygous and control mice were fed a high-fat diet (HFD) for 16 wk. At baseline, the body weight and glucose tolerance of GSK-3α heterozygous and controls were comparable. In contrast, at baseline, a modest but significantly higher body weight (higher lean mass) was seen in GSK-3β heterozygous compared with controls. Post-HFD, GSK-3α heterozygous and controls displayed a comparable phenotype. However, GSK-3β heterozygous were significantly protected against obesity-induced glucose intolerance. Interestingly, the improved glucose tolerance in GSK-3β heterozygous animals was dampened with chronic HFD-feeding, likely due to significantly higher fat mass and lower lean mass in the GSK-3β animals. These findings suggest that GSK-3β is the dominant isoform in glucose metabolism. However, to avail the metabolic benefits of GSK-3β inhibition, it is critical to maintain a healthy weight.<b>NEW & NOTEWORTHY</b> The precise isoform-specific role of GSK-3 in obesity-induced glucose intolerance is unclear. To overcome the limitations of pharmacological GSK-3 inhibitors (not isoform-specific) and tissue-specific genetic models, in the present study, we created novel inducible heterozygous mouse models of GSK-3 inhibition that allowed us to delete the gene globally in an isoform-specific and temporal manner to determine the isoform-specific role of GSK-3 in obesity-induced glucose intolerance.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1349-C1358"},"PeriodicalIF":5.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IQGAP-2: a novel interacting partner with the human colonic thiamin pyrophosphate transporter.","authors":"Kalidas Ramamoorthy, Subrata Sabui, George Kim, James M Flekenstein, Alaullah Sheikh, Hamid M Said","doi":"10.1152/ajpcell.00484.2024","DOIUrl":"10.1152/ajpcell.00484.2024","url":null,"abstract":"<p><p>The human colonic thiamin pyrophosphate transporter (hcTPPT) mediates the uptake of the microbiota-generated and phosphorylated form of vitamin B₁ (i.e., thiamin pyrophosphate) in the large intestine. Expression of hcTPPT along the absorptive tract is restricted to the large intestine, and the transporter is exclusively localized at the apical membrane domain of the polarized epithelial cells/colonocytes. Previous studies have characterized different physiological/pathophysiological aspects of the hcTPPT system, but nothing is currently known on whether the transporter has interacting partner(s) that affect its physiology/biology. We addressed this issue using a Y2H to screen a human colonic cDNA library and have identified three putative interactors, namely IQGAP-2, SNX-6, and DMXL-1. Focusing on IQGAP-2 (whose expression in human colonocytes is the highest), we found (using fluorescent microscopy imaging and coimmunoprecipitation approaches) the putative interactor to colocalize with hcTPPT and to directly interact with the transporter. Also, overexpressing IQGAP-2 in NCM460 cells and in human primary differentiated colonoid monolayers was found to lead to significant (<i>P</i> < 0.01) induction in TPP uptake, while knocking down (using gene-specific siRNAs) caused significant (<i>P</i> < 0.01 and <i>P</i> < 0.05) decrease in uptake. Furthermore, overexpressing IQGAP-2 in NCM460 cells was found to lead to a significant enhancement in hcTPPT protein stability. Finally, we found the expression of IQGAP-2 to be markedly suppressed in conditions/factors that negatively impact colonic TPP uptake. These results identify the IQGAP-2 as an interacting partner with the hcTPPT in human colonocytes and show that this interaction has physiological and biological consequences.<b>NEW & NOTEWORTHY</b> This study reports on the identification of IQGAP-2 as an interacting partner with the hcTPPT in human colonocytes and how that impacts the transporter's physiology and cell biology.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1451-C1461"},"PeriodicalIF":5.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homeostatic regulation of brain activity: from endogenous mechanisms to homeostatic nanomachines.","authors":"Caterina Michetti, Fabio Benfenati","doi":"10.1152/ajpcell.00470.2024","DOIUrl":"10.1152/ajpcell.00470.2024","url":null,"abstract":"<p><p>After the initial concepts of the constancy of the internal milieu or homeostasis, put forward by Claude Bernard and Walter Cannon, homeostasis emerged as a mechanism to control oscillations of biologically meaningful variables within narrow physiological ranges. This is a primary need in the central nervous system that is continuously subjected to a multitude of stimuli from the internal and external environments that affect its function and structure, allowing to adapt the individual to the ever-changing daily conditions. Preserving physiological levels of activity despite disturbances that could either depress neural computation or excessively stimulate neural activity is fundamental, and failure of these homeostatic mechanisms can lead to brain diseases. In this review, we cover the role and main mechanisms of homeostatic plasticity involving the regulation of excitability and synaptic strength from the single neuron to the network level. We analyze the relationships between homeostatic and Hebbian plasticity and the conditions under which the preservation of the excitatory/inhibitory balance fails, triggering epileptogenesis and eventually epilepsy. Several therapeutic strategies to cure epilepsy have been designed to strengthen homeostasis when endogenous homeostatic plasticity mechanisms have become insufficient or ineffective to contrast hyperactivity. We describe \"on demand\" gene therapy strategies, including optogenetics, chemogenetics, and chemo-optogenetics, and particularly focus on new closed loop sensor-actuator strategies mimicking homeostatic plasticity that can be endogenously expressed to strengthen the homeostatic defenses against brain diseases.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1384-C1399"},"PeriodicalIF":5.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}