bioRxiv : the preprint server for biology最新文献

{"title":"Relationship between melanoma vemurafenib tolerance thresholds and metabolic pathway choice and Wnt signaling involvement.","authors":"Pratima Nangia-Makker, Madison Ahrens, Neeraja Purandare, Siddhesh Aras, Jing Li, Katherine Gurdziel, Hyejeong Jang, Seongho Kim, Malathy P Shekhar","doi":"10.1101/2025.03.06.641924","DOIUrl":"10.1101/2025.03.06.641924","url":null,"abstract":"<p><p>Vemurafenib constitutes an important therapeutic for BRAFV600 mutant melanomas, but despite high initial response rates, resistance to BRAF and MEK inhibitors quickly develops. Here, we performed an integrative analysis of metabolomic consequences and transcriptome alterations to uncover mechanisms involved in adaptive vemurafenib resistance (VemR) development and their relationship with vemurafenib tolerance thresholds. We developed BRAFV600E isogenic models of VemR utilizing M14 and A2058 lines, and patient-derived melanomas with V600E or normal BRAF to verify vemurafenib selectivity. MEK or PI3K inhibitors only partially inhibited VemR cell proliferation, indicating cross-resistance to these inhibitors. MITF and β-catenin levels were induced and treatment with Wnt/β-catenin inhibitor ICG-001 restored vemurafenib sensitivity with concomitant reductions in β-catenin-regulated gene expressions, phospho-ERK1/2, and VemR-induced mitochondrial mass and respiration. Targeted metabolite, MitoPlate-S1, Mito-stress and transcriptome/metabolomic analysis showed that melanoma cells with elevated vemurafenib tolerance thresholds such as A2058 VemR cells utilize Wnt/β-catenin signaling for mitochondrial metabolism while VemR cells with low tolerance such as M14 VemR cells rely on Wnt/β-catenin signaling for pentose phosphate pathway. Pathways associated with cytokine-cytokine receptor, ECM receptor, and neuroactive ligand receptor interactions were similarly enriched in BRAFV600E patient-derived melanoma as M14 and A2058 cells whereas distinct pathways involving cell cycle, DNA replication, Fanconi anemia and DNA repair pathways are upregulated in wild type BRAF expressing patient derived melanoma. These data show for the first time that the metabolic pathway choices made by VemR BRAF mutant melanomas are controlled by vemurafenib tolerance and endurance thresholds and Wnt/β-catenin signaling plays a central role in coordinating expression of genes controlling VemR and metabolic pathway shifts.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic risk in endolysosomal network genes correlates with endolysosomal dysfunction across neural cell types in Alzheimer's disease.","authors":"Sainath Mamde, Shannon Rose, Katherine E Prater, Alexandra Cochoit, Yu Fan Lin, Isa Smith, Corbin Scott Clarke Johnson, Aquene Reid, Wei Qiu, Sam Strohbehn, C Dirk Keene, Brad Rolf, Kevin Lin, Su-In Lee, Gwenn Garden, Elizabeth Blue, Jessica E Young, Suman Jayadev","doi":"10.1101/2025.03.16.643481","DOIUrl":"10.1101/2025.03.16.643481","url":null,"abstract":"<p><p>Late-onset Alzheimer's disease (LOAD) has a complex genomic architecture with risk variants in multiple pathways, including the endolysosomal network (ELN). Whether genetic risk in specific pathways correlates with corresponding biological dysfunction remains largely unknown. We developed an endolysosomal pathway-specific polygenic risk score (ePRS) using 13 established AD GWAS loci containing ELN genes. We investigated the association between ePRS and AD neuropathology, then examined cell-specific endolysosomal morphology and transcriptomic profiles in post-mortem dorsolateral prefrontal cortex samples from donors stratified by ePRS burden. We found that the ePRS was significantly associated with AD diagnosis and neuropathological measures, comparable to a pathway-agnostic PRS despite representing far fewer loci. High ePRS correlated with increased neuronal endosome volume, number and perinuclear aggregation, as well as enlarged microglial lysosomes, independent of AD pathology. Single-nucleus RNA sequencing revealed cell-type transcriptomic changes associated with ePRS status, including glutamatergic signaling, protein homeostasis, responses to DNA damage and immune function. Neurons, astrocytes, oligodendrocytes, and microglia showed varied gene expression patterns associated with ePRS burden. Conclusions: This study provides evidence that AD genetic risk variants harboring ELN genes correlate with endolysosomal dysfunction in human brain tissue. These findings suggest that pathway-specific genetic risk contributes to corresponding cellular pathology in AD and nominates candidate mechanisms by which ELN AD variants contribute to pathogenesis.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PMS2 has both pro-mutagenic and anti-mutagenic effects on repeat instability in the Repeat Expansion Diseases.","authors":"Diego Antonio Jimenez, Carson J Miller, Alexandra Walker, Kusala Anupindi, Karen Usdin, Xiaonan Zhao","doi":"10.1101/2024.08.13.607839","DOIUrl":"10.1101/2024.08.13.607839","url":null,"abstract":"<p><p>Expansion of a disease-specific tandem repeat is responsible for >45 Repeat Expansion Diseases (REDs). The mismatch repair protein PMS2 is a modifier of somatic expansion and disease severity in Huntington's disease (HD), a RED resulting from a CAG-repeat expansion. However, PMS2 shows different effects in different RED models, protecting against expansion in some and promoting it in others. To better understand this difference, we carried out a systematic study of the loss of PMS2 in mouse models of HD and the fragile X-related disorders (FXDs), a group of REDs resulting from a CGG-repeat expansion. In both models, loss of one Pms2 allele resulted in more expansions, while loss of both alleles resulted in more expansion in some organs but less in others. Thus, rather than reflecting different expansion mechanisms in different diseases, the previously reported differences in different model systems likely reflects the ability of PMS2 to promote expansion in some cellular contexts and to protect against it in others. In mouse embryonic stem cells containing both sets of repeats where PMS2 was expressed under the control of a doxycycline (DOX)-inducible promoter, low DOX concentrations produced a dose-dependent increase in expansions of both repeats, an effect that was dependent on the PMS2 nuclease domain, while higher DOX levels resulted in a decrease in expansions. Our findings have implications both for the mechanism of expansion and for therapeutic approaches to treat these diseases by reducing somatic expansion.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCDC32 stabilizes clathrin-coated pits and drives their invagination.","authors":"Ziyan Yang, Changsong Yang, Zheng Huang, Peiliu Xu, Yueping Li, Lu Han, Linyuan Peng, Xiangying Wei, John Pak, Tatyana Svitkina, Sandra L Schmid, Zhiming Chen","doi":"10.1101/2024.06.26.600785","DOIUrl":"10.1101/2024.06.26.600785","url":null,"abstract":"<p><p>Clathrin-mediated endocytosis (CME) is essential for maintaining cellular homeostasis. Previous studies have reported more than 50 CME accessory proteins; however, the mechanism driving the invagination of clathrin-coated pits (CCPs) remains elusive. We show by quantitative live cell imaging that siRNA-mediated knockdown of CCDC32, a poorly characterized endocytic accessory protein, leads to the accumulation of unstable flat clathrin assemblies. CCDC32 interacts with the alpha-appendage domain (AD) of AP2 in vitro and with full length AP2 complexes in cells. Deletion of aa78-98 in CCDC32, corresponding to a predicted alpha-helix, abrogates AP2 binding and CCDC32's early function in CME. Furthermore, clinically observed nonsense mutations in CCDC32, which result in C-terminal truncations that lack aa78-98, are linked to the development of cardio-facio-neuro-developmental syndrome (CFNDS). Overall, our data demonstrate the function of a novel endocytic accessory protein, CCDC32, in regulating CCP stabilization and invagination, critical early stages of CME.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11230434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141560730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pcdh20 is a POU2F3 target gene required for proper tuft cell microvillus formation.","authors":"Katherine E Ankenbauer, Yilin Yang, Chi-Yeh Chung, Leonardo R Andrade, Sammy Weiser Novak, Brenda Jarvis, Wahida H Ali Hanel, Jiayue Liu, Victoria Sarkisian, Neil Dani, Evan Krystofiak, Gaizun Hu, Seham Ebrahim, Bechara Kachar, Qizhi Gong, Geoffrey Wahl, Uri Manor, Ken Lau, Kathleen E DelGiorno","doi":"10.1101/2025.03.18.644042","DOIUrl":"10.1101/2025.03.18.644042","url":null,"abstract":"<p><p>Tuft cells are solitary chemosensory cells known for their distinct tall, blunt microvilli, thought to be analogous to mechanosensory hair cell stereocilia. Identification of commonalities between tuft and hair cells could identify a role for tuft cells in mechanotransduction. Transcription factor POU2F3 is the master regulator of tuft cell formation, however how POU2F3 drives formation of this unique cell and the functional role of the microvillar apparatus is unknown. POU2F3 ChIP-seq was performed on isolated tuft cells and compared to the cochlear hair cell transcriptome. Structural genes common to both tuft and hair cells, including protocadherin 20 (PCDH20), were identified. Immunogold labeling and imaging localized PCDH20 to extensive intermicrovillar linkages in tuft cells. Knockdown of PCDH20 in mice resulted in impaired microvilli formation and a disruption in structure. Altogether, PCDH20 is a POU2F3 target gene in tuft cells critical to maintain the rigid microvillar apparatus, which may function in mechanotransduction.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The bacterial chaperone CsgC inhibits functional amyloid CsgA formation by promoting the intrinsically disordered pre-nuclear state.","authors":"Anthony Balistreri, Divya Kolli, Sanduni Wasana Jayaweera, Daniel Lundahl, Yilin Han, Lily Kalcec, Emily Goetzler, Rachel Alessio, Brandon Ruotolo, Anders Olofsson, Matthew R Chapman","doi":"10.1101/2025.03.21.644623","DOIUrl":"10.1101/2025.03.21.644623","url":null,"abstract":"<p><p><i>E. coli</i> secretes a functional amyloid called curli during biofilm formation. Curli fibers are composed of polymers of the CsgA protein, which adopts a beta-sheet rich fold upon fibrillization. A chaperone-like protein called CsgC inhibits CsgA amyloid formation. Like other amyloidogenic proteins, CsgA undergoes a 3-stage aggregation process: an initial lag phase where a beta-rich nucleus forms, an exponential elongation phase, and a plateau phase. It is currently not known if CsgC inhibits amyloid formation by inhibiting formation of the pre-fibril nucleus, or rather, if CsgC inhibits a later stage of amyloid formation by blocking monomer addition to a growing fiber. Here, CsgC homologs from <i>C. youngae</i> , <i>C. davisae</i> , and <i>H. alvei</i> were purified and characterized for their ability to interrogate CsgA amyloid formation. Each of the CsgC homologs prolonged the lag phase of <i>E. coli</i> CsgA amyloid formation in a similar fashion as <i>E. coli</i> CsgC. Additionally, we found that <i>E. coli</i> CsgC interacted transiently and weakly with a monomeric, pre-nucleus species of CsgA and that this interaction delayed amyloid formation. A transient CsgC-CsgA heterodimer was observed using ion mobility-mass spectrometry. When CsgC was added to actively polymerizing CsgA, exponential growth commonly associated with nucleation-dependent amyloid formation was lost. However, the addition of preformed CsgA seeds did not rescue exponential growth indicating that CsgC also has inhibitory activity during fibril elongation. Indeed, CsgC interacted strongly with CsgA fibers, suggesting that the interaction between CsgC and CsgA fibers can slow new fiber growth. CsgC displays a unique inhibitory activity at multiple stages of amyloid formation. CsgC acts as an energy-independent chaperone that transiently interacts with prefibrillar CsgA as well as an amyloid fiber.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preferred spatial frequency covaries with cortical magnification in human primary visual cortex.","authors":"Marc M Himmelberg, Yuna M Kwak, Marisa Carrasco, Jonathan Winawer","doi":"10.1101/2025.03.19.644195","DOIUrl":"10.1101/2025.03.19.644195","url":null,"abstract":"<p><p>Primary visual cortex (V1) has played a key role in understanding the organization of cerebral cortex. Both structural and functional properties vary sharply throughout the human V1 map. Despite large variation, underlying constancies computed from the covariation pattern of V1 properties have been proposed. Such constancies would imply that V1 is composed of multiple identical units whose visual properties differ only due to differences in their inputs. To test this, we used fMRI to investigate how V1 cortical magnification and preferred spatial frequency covary across eccentricity and polar angle, and across individual observers (n=40). The two properties correlated across individuals, such that those with higher overall cortical magnification (i.e., larger V1 maps) had higher preferred spatial frequency (integrated across the map). Although correlated, the two properties were not proportional, and hence their ratio (mm of cortex per stimulus cycle) was not constant. Cortical magnification and preferred spatial frequency were strongly correlated across eccentricity and across polar angle, however their relation differed between these dimensions: they were proportional across eccentricity but not polar angle. The constant ratio of cortical magnification to preferred spatial frequency across eccentricity suggests a shared underlying cause of variation in the two properties, e.g., the gradient of retinal ganglion cell density across eccentricity. In contrast, the deviation from proportionality around polar angle implies that cortical variation differs from that in retina along this dimension. Thus, a constancy hypothesis is supported for one of the two spatial dimensions of V1, highlighting the importance of examining the full 2D-map, in multiple individuals, to understand how V1 is organized.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Behavioral timescale synaptic plasticity in the hippocampus creates non-spatial representations during learning and is modulated by entorhinal inputs.","authors":"Conor C Dorian, Jiannis Taxidis, Ahmet Arac, Peyman Golshani","doi":"10.1101/2024.08.27.609983","DOIUrl":"10.1101/2024.08.27.609983","url":null,"abstract":"<p><p>Behavioral timescale synaptic plasticity (BTSP) is a form of synaptic potentiation where a single plateau potential in hippocampal neurons forms a place field during spatial learning. We asked whether BTSP can also form non-spatial responses in the hippocampus and what roles the medial and lateral entorhinal cortex (MEC and LEC) play in driving non-spatial BTSP. Two-photon calcium imaging of dorsal CA1 neurons while mice performed an odor-cued working memory task revealed plateau-like events which formed stable odor-specific responses. These BTSP-like events were much more frequent during the first day of task learning, suggesting that BTSP may be important for early learning. Strong single-neuron stimulation through holographic optogenetics induced plateau-like events and subsequent odor-fields, causally linking BTSP with non-spatial representations. MEC chemogenetic inhibition reduced the frequency of plateau-like events, whereas LEC inhibition reduced potentiation and field-induction probability. Calcium imaging of LEC and MEC temporammonic CA1 projections revealed that MEC axons were more strongly activated by odor presentations, while LEC axons were more odor-selective, further confirming the role of MEC in driving plateau-like events and LEC in relaying odor-specific information. Altogether, odor-specific information from LEC and strong odor-timed activity from MEC are crucial for driving BTSP in CA1, which is a synaptic plasticity mechanism for generation of both spatial and non-spatial responses in the hippocampus.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11383060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Kinesin-14 Tail: Dual microtubule binding domains drive spindle morphogenesis through tight microtubule cross-linking and robust sliding.","authors":"Stephanie C Ems-McClung, MacKenzie Cassity, Anjaly Prasannajith, Claire E Walczak","doi":"10.1101/2025.02.25.640188","DOIUrl":"10.1101/2025.02.25.640188","url":null,"abstract":"<p><p>Proper spindle assembly requires the Kinesin-14 family of motors to organize microtubules (MTs) into the bipolar spindle by cross-linking and sliding anti-parallel and parallel MTs through their motor and tail domains. How they mediate these different activities is unclear. We identified two MT binding domains (MBD1 and MBD2) within the Xenopus Kinesin-14 XCTK2 tail and found that MBD1 MT affinity was weaker than MBD2. Comparable to full-length GFP-XCTK2 wild-type protein (GX-WT), GFP-XCTK2 containing the MBD1 mutations (GX-MBD1mut) stimulated spindle assembly, localized moderately on the spindle, and formed narrow spindles. In contrast, GX-MBD2mut only partially stimulated spindle assembly, localized weakly on the spindle, and formed shorter spindles. Biochemical reconstitution of MT cross-linking and sliding demonstrated that GX-MBD2mut slid anti-parallel MTs faster than GX-WT and GX-MBD1mut. However, GX-WT and GX-MBD1mut statically cross-linked the majority of parallel MTs, whereas GX-MBD2mut equally slid and statically cross-linked parallel MTs without affecting their sliding velocity. These results provide a mechanism by which the two different MT binding domains in the Kinesin-14 tail balance anti-parallel MT sliding velocity (MBD1) and tight parallel MT cross-linking (MBD2), which are important for spindle assembly and localization, and provide a basis for characterizing how molecular motors organize MTs within the spindle.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On-Demand Seizures Facilitate Rapid Screening of Therapeutics for Epilepsy.","authors":"Yuzhang Chen, Brian Litt, Flavia Vitale, Hajime Takano","doi":"10.1101/2024.08.26.609726","DOIUrl":"10.1101/2024.08.26.609726","url":null,"abstract":"<p><p>Animal models of epilepsy are critical in drug development and therapeutic testing, but dominant methods for pharmaceutical evaluation face a tradeoff between higher throughput and etiological relevance. For example, in temporal lobe epilepsy, a type of epilepsy where seizures originate from limbic structures like the hippocampus, the main screening models are either based on acutely induced seizures in wild type, naïve animals or spontaneous seizures in chronically epileptic animals. Both types have their disadvantages - the acute convulsant or kindling induced seizures do not account for the myriad neuropathological changes in the diseased, epileptic brains, and spontaneous behavioral seizures are sparse in the chronically epileptic models, making it time-intensive to sufficiently power experiments. In this study, we took a mechanistic approach to precipitate seizures \"on demand\" in chronically epileptic mice. We briefly synchronized principal cells in the CA1 region of the diseased hippocampus to reliably induce stereotyped on-demand behavioral seizures. These induced seizures resembled naturally occurring spontaneous seizures in the epileptic animals and could be stopped by commonly prescribed anti-seizure medications such as levetiracetam and diazepam. Furthermore, we showed that seizures induced in chronically epileptic animals differed from those in naïve animals, highlighting the importance of evaluating therapeutics in the diseased circuit. Taken together, we envision our model to advance the speed at which both pharmacological and closed loop interventions for temporal lobe epilepsy are evaluated.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11507747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}