{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T11:37:02Z","timestamp":1782819422148,"version":"3.54.5"},"reference-count":99,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01-AG049772"],"award-info":[{"award-number":["R01-AG049772"]}]},{"name":"National Institutes of Health","award":["R01-AG058467"],"award-info":[{"award-number":["R01-AG058467"]}]},{"name":"National Institutes of Health","award":["R01-NS120327"],"award-info":[{"award-number":["R01-NS120327"]}]},{"name":"National Institutes of Health","award":["R01-AG072703"],"award-info":[{"award-number":["R01-AG072703"]}]},{"name":"National Institutes of Health","award":["R61-NS124923"],"award-info":[{"award-number":["R61-NS124923"]}]},{"name":"National Institutes of Health","award":["R01-MH113986"],"award-info":[{"award-number":["R01-MH113986"]}]},{"name":"National Institutes of Health","award":["R21-NS101703"],"award-info":[{"award-number":["R21-NS101703"]}]},{"name":"National Institutes of Health","award":["R01EY030863"],"award-info":[{"award-number":["R01EY030863"]}]},{"name":"National Institutes of Health","award":["3R01EY030863-02S1"],"award-info":[{"award-number":["3R01EY030863-02S1"]}]},{"name":"National Institutes of Health","award":["3R01EY030863-03S1"],"award-info":[{"award-number":["3R01EY030863-03S1"]}]},{"name":"National Institutes of Health grant National Eye Institute (NEI)","award":["R01-AG049772"],"award-info":[{"award-number":["R01-AG049772"]}]},{"name":"National Institutes of Health grant National Eye Institute (NEI)","award":["R01-AG058467"],"award-info":[{"award-number":["R01-AG058467"]}]},{"name":"National Institutes of Health grant National Eye Institute (NEI)","award":["R01-NS120327"],"award-info":[{"award-number":["R01-NS120327"]}]},{"name":"National Institutes of Health grant National Eye Institute (NEI)","award":["R01-AG072703"],"award-info":[{"award-number":["R01-AG072703"]}]},{"name":"National Institutes of Health grant National Eye Institute (NEI)","award":["R61-NS124923"],"award-info":[{"award-number":["R61-NS124923"]}]},{"name":"National Institutes of Health grant National Eye Institute (NEI)","award":["R01-MH113986"],"award-info":[{"award-number":["R01-MH113986"]}]},{"name":"National Institutes of Health grant National Eye Institute (NEI)","award":["R21-NS101703"],"award-info":[{"award-number":["R21-NS101703"]}]},{"name":"National Institutes of Health grant National Eye Institute (NEI)","award":["R01EY030863"],"award-info":[{"award-number":["R01EY030863"]}]},{"name":"National Institutes of Health grant National Eye Institute (NEI)","award":["3R01EY030863-02S1"],"award-info":[{"award-number":["3R01EY030863-02S1"]}]},{"name":"National Institutes of Health grant National Eye Institute (NEI)","award":["3R01EY030863-03S1"],"award-info":[{"award-number":["3R01EY030863-03S1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>To investigate how dysregulated transient receptor potential canonical channels (TRPCs) are associated with Alzheimer\u2019s disease (AD), we challenged primary neurons with amyloid-\u03b2 (A\u03b2). Both the naturally secreted or synthetic A\u03b2 oligomers (A\u03b2Os) induced long-lasting increased TRPC3 and downregulated the TRPC6 expression in mature excitatory neurons (CaMKII\u03b1-high) via a Ca2+-dependent calcineurin-coupled NFAT transcriptionally and calpain-mediated protein degradation, respectively. The TRPC3 expression was also found to be upregulated in pyramidal neurons of human AD brains. The selective downregulation of the Trpc6 gene induced synaptotoxicity, while no significant effect was observed from the Trpc3-targeting siRNA, suggesting potentially differential roles of TRPC3 and 6 in modulating the synaptic morphology and functions. Electrophysiological recordings of mouse hippocampal slices overexpressing TRPC3 revealed increased neuronal hyperactivity upon the TRPC3 channel activation by its agonist. Furthermore, the A\u03b2O-mediated synaptotoxicity appeared to be positively correlated with the degrees of the induced dendritic Ca2+ flux in neurons, which was completely prevented by the co-treatment with two pyrazole-based TRPC3-selective antagonists Pyr3 or Pyr10. Taken together, our findings suggest that the aberrantly upregulated TRPC3 is another ion channel critically contributing to the process of A\u03b2O-induced Ca2+ overload, neuronal hyperexcitation, and synaptotoxicity, thus representing a potential therapeutic target of AD.<\/jats:p>","DOI":"10.3390\/cells14110843","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T11:14:12Z","timestamp":1749035652000},"page":"843","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Soluble \u03b2-Amyloid Oligomers Selectively Upregulate TRPC3 in Excitatory Neurons via Calcineurin-Coupled NFAT"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2326-4167","authenticated-orcid":false,"given":"Zhengjun","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyi","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3202-2402","authenticated-orcid":false,"given":"Jiaxing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Genetics, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingming","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moumita","family":"Khamrai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9422-2450","authenticated-orcid":false,"given":"Yuyang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Ishii","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, UConn Health, Farmington, CT 06030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6509-216X","authenticated-orcid":false,"given":"Kazuko","family":"Sakata","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9522-4474","authenticated-orcid":false,"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4342-0975","authenticated-orcid":false,"given":"Jianyang","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7686-5284","authenticated-orcid":false,"given":"Thirumalini","family":"Vaithianathan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"},{"name":"Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8313-3770","authenticated-orcid":false,"given":"Fu-Ming","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca-Fang","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13024-019-0333-5","article-title":"The neuropathological diagnosis of Alzheimer\u2019s disease","volume":"14","author":"DeTure","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.cell.2019.09.001","article-title":"Alzheimer disease: An update on pathobiology and treatment strategies","volume":"179","author":"Long","year":"2019","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/s43587-023-00404-2","article-title":"Towards a future where Alzheimer\u2019s disease pathology is stopped before the onset of dementia","volume":"3","author":"Smets","year":"2023","journal-title":"Nat. Aging"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s disease: The amyloid cascade hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S567","DOI":"10.3233\/JAD-179941","article-title":"The amyloid-\u03b2 oligomer hypothesis: Beginning of the third decade","volume":"64","author":"Cline","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6448","DOI":"10.1073\/pnas.95.11.6448","article-title":"Diffusible, nonfibrillar ligands derived from A\u03b21\u201342 are potent central nervous system neurotoxins","volume":"95","author":"Lambert","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1126\/science.1074069","article-title":"Alzheimer\u2019s disease is a synaptic failure","volume":"298","author":"Selkoe","year":"2002","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/1750-1326-6-63","article-title":"Alzheimer\u2019s disease: Synapses gone cold","volume":"6","author":"Koffie","year":"2011","journal-title":"Mol. Neurodegener."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"a006338","DOI":"10.1101\/cshperspect.a006338","article-title":"Neurotoxicity of amyloid \u03b2-protein: Synaptic and network dysfunction","volume":"2","author":"Mucke","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/1750-1326-9-48","article-title":"Oligomeric A\u03b2-induced synaptic dysfunction in Alzheimer\u2019s disease","volume":"9","author":"Tu","year":"2014","journal-title":"Mol. Neurodegener."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1002\/1531-8249(199912)46:6<860::AID-ANA8>3.0.CO;2-M","article-title":"Soluble pool of A\u03b2 amyloid as a determinant of severity of neurodegeneration in Alzheimer\u2019s disease","volume":"46","author":"McLean","year":"1999","journal-title":"Ann. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/S0002-9440(10)65184-X","article-title":"Soluble amyloid \u03b2 peptide concentration as a predictor of synaptic change in Alzheimer\u2019s disease","volume":"155","author":"Lue","year":"1999","journal-title":"Am. J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1001\/jama.283.12.1571","article-title":"Correlation between elevated levels of amyloid \u03b2-peptide in the brain and cognitive decline","volume":"283","author":"Haroutunian","year":"2000","journal-title":"JAMA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"32046","DOI":"10.1074\/jbc.M201750200","article-title":"Oligomeric and fibrillar species of amyloid-\u03b2 peptides differentially affect neuronal viability","volume":"277","author":"Dahlgren","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.mcn.2006.07.011","article-title":"Amyloid \u03b2 peptide adversely affects spine number and motility in hippocampal neurons","volume":"33","author":"Shrestha","year":"2006","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.1523\/JNEUROSCI.4970-06.2007","article-title":"Natural oligomers of the Alzheimer amyloid-\u03b2 protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway","volume":"27","author":"Shankar","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/j.neuron.2009.05.012","article-title":"Soluble oligomers of amyloid \u03b2 protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake","volume":"62","author":"Li","year":"2009","journal-title":"Neuron"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/nn1372","article-title":"Natural oligomers of the amyloid-\u03b2 protein specifically disrupt cognitive function","volume":"8","author":"Cleary","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association Calcium Hypothesis Workgroup, and Khachaturian, Z.S. (2017). Calcium hypothesis of Alzheimer\u2019s disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimer\u2019s Dement., 13, 178\u2013182.e17.","DOI":"10.1016\/j.jalz.2016.12.006"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17294","DOI":"10.1074\/jbc.M500997200","article-title":"Calcium Dysregulation and Membrane Disruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers","volume":"280","author":"Demuro","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1007\/s11427-011-4205-7","article-title":"Early calcium dysregulation in Alzheimer\u2019s disease: Setting the stage for synaptic dysfunction","volume":"54","author":"Chakroborty","year":"2011","journal-title":"Sci. China Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Liu, J., Chang, L., Song, Y., Li, H., and Wu, Y. (2019). The role of NMDA receptors in Alzheimer\u2019s disease. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00043"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/S0092-8674(02)00670-0","article-title":"The TRP channels, a remarkably functional family","volume":"108","author":"Montell","year":"2002","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1146\/annurev.physiol.68.040204.100431","article-title":"An introduction to TRP channels","volume":"68","author":"Ramsey","year":"2006","journal-title":"Annu. Rev. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s00424-008-0618-y","article-title":"Functional roles of TRPC channels in the developing brain","volume":"458","author":"Tai","year":"2009","journal-title":"Pfl\u00fcgers Arch.-Eur. J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gualdani, R., and Gailly, P. (2020). How TRPC channels modulate hippocampal function. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113915"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1152\/physrev.00021.2006","article-title":"Transient receptor potential cation channels in disease","volume":"87","author":"Nilius","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chen, X., Sooch, G., Demaree, I.S., White, F.A., and Obukhov, A.G. (2020). Transient receptor potential canonical (TRPC) channels: Then and now. Cells, 9.","DOI":"10.3390\/cells9091983"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.bbadis.2007.03.006","article-title":"Transient receptor potential channels in Alzheimer\u2019s disease","volume":"1772","author":"Yamamoto","year":"2007","journal-title":"Biochim. Biophys. Acta-Mol. Basis Dis."},{"key":"ref_31","first-page":"94","article-title":"TRPC channels and their implications for neurological diseases","volume":"9","author":"Selvaraj","year":"2010","journal-title":"CNS Neurol. Disord.-Drug Targets Former. Curr. Drug Targets-CNS Neurol. Disord."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1146\/annurev.pharmtox.48.113006.094928","article-title":"The TRPC class of ion channels: A critical review of their roles in slow, sustained increases in intracellular Ca2+ concentrations","volume":"49","author":"Birnbaumer","year":"2009","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"455","DOI":"10.3390\/cells3020455","article-title":"Physiological function and characterization of TRPCs in neurons","volume":"3","author":"Sun","year":"2014","journal-title":"Cells"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Li, J.J., Dolios, G., Wang, R., and Liao, F.-F. (2014). Soluble beta-amyloid peptides, but not insoluble fibrils, have specific effect on neuronal microRNA expression. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090770"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1523\/JNEUROSCI.0151-13.2014","article-title":"Hsp90 chaperone inhibitor 17-AAG attenuates A\u03b2-induced synaptic toxicity and memory impairment","volume":"34","author":"Chen","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1038\/mp.2016.104","article-title":"A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer\u2019s mouse model via an HSF1-mediated mechanism","volume":"22","author":"Wang","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9564","DOI":"10.1074\/jbc.270.16.9564","article-title":"Aggregation of Secreted Amyloid \u03b2-Protein into Sodium Dodecyl Sulfate-stable Oligomers in Cell Culture","volume":"270","author":"Podlisny","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13024-024-00759-z","article-title":"Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer\u2019s disease","volume":"19","author":"Ishii","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.1152\/jn.00305.2011","article-title":"Molecular and functional differences in voltage-activated sodium currents between GABA projection neurons and dopamine neurons in the substantia nigra","volume":"106","author":"Ding","year":"2011","journal-title":"J. Neurophysiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1021\/acsmedchemlett.0c00571","article-title":"Discovery of a highly selective and potent TRPC3 inhibitor with high metabolic stability and low toxicity","volume":"12","author":"Zhang","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/416535a","article-title":"Naturally secreted oligomers of amyloid \u03b2 protein potently inhibit hippocampal long-term potentiation in vivo","volume":"416","author":"Walsh","year":"2002","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/nm1234","article-title":"Amyloid \u03b2 protein immunotherapy neutralizes A\u03b2 oligomers that disrupt synaptic plasticity in vivo","volume":"11","author":"Klyubin","year":"2005","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1113\/jphysiol.2005.103754","article-title":"Effects of secreted oligomers of amyloid \u03b2-protein on hippocampal synaptic plasticity: A potent role for trimers","volume":"572","author":"Townsend","year":"2006","journal-title":"J. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/nm1782","article-title":"Amyloid-\u03b2 protein dimers isolated directly from Alzheimer\u2019s brains impair synaptic plasticity and memory","volume":"14","author":"Shankar","year":"2008","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1523\/JNEUROSCI.06-03-00714.1986","article-title":"Immunocytochemical localization of tubulin and microtubule-associated protein 2 during the development of hippocampal neurons in culture","volume":"6","author":"Caceres","year":"1986","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.jneumeth.2007.04.021","article-title":"A quantitative method for analysis of in vitro neurite outgrowth","volume":"164","author":"Mitchell","year":"2007","journal-title":"J. Neurosci. Methods"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"DeGiosio, R.A., Grubisha, M.J., MacDonald, M.L., McKinney, B.C., Camacho, C.J., and Sweet, R.A. (2022). More than a marker: Potential pathogenic functions of MAP2. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.974890"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1523\/JNEUROSCI.3501-06.2007","article-title":"A\u03b2 oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer\u2019s disease","volume":"27","author":"Lacor","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5305","DOI":"10.1038\/sj.emboj.7601417","article-title":"TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy","volume":"25","author":"Onohara","year":"2006","journal-title":"EMBO J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/16711","article-title":"Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol","volume":"397","author":"Hofmann","year":"1999","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1161\/CIRCRESAHA.110.225888","article-title":"TRPC channels as effectors of cardiac hypertrophy","volume":"108","author":"Eder","year":"2011","journal-title":"Circ. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"12957","DOI":"10.1523\/JNEUROSCI.1064-09.2009","article-title":"Cognitive decline in Alzheimer\u2019s disease is associated with selective changes in calcineurin\/NFAT signaling","volume":"29","author":"Abdul","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Mackiewicz, J., Lisek, M., and Boczek, T. (2023). Targeting CaN\/NFAT in Alzheimer\u2019s brain degeneration. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1281882"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/S0165-6147(00)89070-7","article-title":"NMDA receptor-dependent excitotoxicity: The role of intracellular Ca2+ release","volume":"16","author":"Mody","year":"1995","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1016\/j.neuron.2022.03.021","article-title":"Functional coupling of TRPM2 and extrasynaptic NMDARs exacerbates excitotoxicity in ischemic brain injury","volume":"110","author":"Zong","year":"2022","journal-title":"Neuron"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"9808","DOI":"10.1073\/pnas.90.21.9808","article-title":"Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity","volume":"90","author":"Dawson","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1146\/annurev.immunol.15.1.707","article-title":"Transcription factors of the NFAT family: Regulation and function","volume":"15","author":"Rao","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3114","DOI":"10.1172\/JCI27702","article-title":"TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling","volume":"116","author":"Kuwahara","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Repnik, U., \u010cesen, M.H., and Turk, B. (2013). The endolysosomal system in cell death and survival. Cold Spring Harb. Perspect. Biol., 5.","DOI":"10.1101\/cshperspect.a008755"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1002\/(SICI)1098-1063(1996)6:4<347::AID-HIPO1>3.0.CO;2-I","article-title":"Interneurons of the hippocampus","volume":"6","author":"Freund","year":"1996","journal-title":"Hippocampus"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/nature03477","article-title":"Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor","volume":"434","author":"Li","year":"2005","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1242\/jcs.026906","article-title":"TRPC6 channels promote dendritic growth via the CaMKIV-CREB pathway","volume":"121","author":"Tai","year":"2008","journal-title":"J. Cell science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nn.2127","article-title":"Critical role of TRPC6 channels in the formation of excitatory synapses","volume":"11","author":"Zhou","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"11837","DOI":"10.1523\/JNEUROSCI.1188-16.2016","article-title":"Store-operated calcium channel complex in postsynaptic spines: A new therapeutic target for Alzheimer\u2019s disease treatment","volume":"36","author":"Zhang","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"15415","DOI":"10.3390\/ijms242015415","article-title":"Role of neuronal TRPC6 channels in synapse development, memory formation and animal behavior","volume":"24","author":"Zerov","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1111\/j.1476-5381.2012.02126.x","article-title":"Novel pyrazole compounds for pharmacological discrimination between receptor-operated and store-operated Ca2+ entry pathways","volume":"167","author":"Schleifer","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Wang, J., Chen, L., Wang, Z., Zhang, S., Ding, D., Lin, G., Zhang, H., Boda, V.K., Kong, D., and Ortyl, T.C. (2024). TRPC3 suppression ameliorates synaptic dysfunctions and memory deficits in Alzheimer\u2019s disease. bioRxiv.","DOI":"10.1101\/2024.09.16.611061"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1007\/s00401-018-1920-1","article-title":"Sex differences in Alzheimer\u2019s disease and common neuropathologies of aging","volume":"136","author":"Oveisgharan","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1093\/jnen\/nlw047","article-title":"Gender Differences in Alzheimer Disease: Brain Atrophy, Histopathology Burden, and Cognition","volume":"75","author":"Filon","year":"2016","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1101\/gad.1102703","article-title":"Transcriptional regulation by calcium, calcineurin, and NFAT","volume":"17","author":"Hogan","year":"2003","journal-title":"Genes Dev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.neuron.2009.05.007","article-title":"Neural activity regulates synaptic properties and dendritic structure in vivo through calcineurin\/NFAT signaling","volume":"62","author":"Schwartz","year":"2009","journal-title":"Neuron"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6132","DOI":"10.1523\/JNEUROSCI.0877-17.2017","article-title":"Calcineurin\/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in A\u03b2-Bearing Mice","volume":"37","author":"Sompol","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1161\/01.RES.0000109415.17511.18","article-title":"Calcineurin\/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy","volume":"94","author":"Wilkins","year":"2004","journal-title":"Circ. Res."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Nakayama, H., Wilkin, B.J., Bodi, I., and Molkentin, J.D. (2006). Calcineurin-dependent cardiac hypertrophy is activated by TRPC in the adult mouse heart. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol., 20.","DOI":"10.1096\/fj.05-5560com"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41392-023-01651-w","article-title":"Transcriptional co-activators: Emerging roles in signaling pathways and potential therapeutic targets for diseases","volume":"8","author":"Talukdar","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3480","DOI":"10.1172\/JCI43165","article-title":"Inhibition of TRPC6 degradation suppresses ischemic brain damage in rats","volume":"120","author":"Du","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.1016\/j.bbamcr.2015.09.004","article-title":"The Na+\/K+-ATPase and the amyloid-beta peptide a\u03b21\u201340 control the cellular distribution, abundance and activity of TRPC6 channels","volume":"1853","author":"Chauvet","year":"2015","journal-title":"Biochim. Biophys. Acta-Mol. Cell Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1007\/s10753-023-01808-3","article-title":"Transient receptor potential canonical 6 (TRPC6) channel in the pathogenesis of diseases: A jack of many trades","volume":"46","author":"Saqib","year":"2023","journal-title":"Inflammation"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1111\/jnc.12045","article-title":"TRPC 6 inhibited NMDA receptor activities and protected neurons from ischemic excitotoxicity","volume":"123","author":"Li","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Guo, C., Ma, Y., Ma, S., Mu, F., Deng, J., Duan, J., Xiong, L., Yin, Y., Wang, Y., and Xi, M. (2017). The role of TRPC6 in the neuroprotection of calycosin against cerebral ischemic injury. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-03404-6"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Shekhar, S., Liu, Y., Wang, S., Zhang, H., Fang, X., Zhang, J., Fan, L., Zheng, B., Roman, R.J., and Wang, Z. (2021). Novel mechanistic insights and potential therapeutic impact of TRPC6 in neurovascular coupling and ischemic stroke. Int. J. Mol. Sci., 22.","DOI":"10.20944\/preprints202101.0458.v1"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Chen, J., Li, Z., Hatcher, J.T., Chen, Q.-H., Chen, L., Wurster, R.D., Chan, S.L., and Cheng, Z. (2017). Deletion of TRPC6 attenuates NMDA receptor-mediated Ca2+ entry and Ca2+-induced neurotoxicity following cerebral ischemia and oxygen-glucose deprivation. Front. Neurosci., 11.","DOI":"10.3389\/fnins.2017.00138"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/mp.2014.141","article-title":"Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons","volume":"20","author":"Acab","year":"2015","journal-title":"Mol. Psychiatry"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"7297","DOI":"10.1007\/s12035-023-03527-0","article-title":"Deletion of TRPC6, an autism risk gene, induces hyperexcitability in cortical neurons derived from human pluripotent stem cells","volume":"60","author":"Shin","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1113\/JP273327","article-title":"Differences in TRPC3 and TRPC6 channels assembly in mesenteric vascular smooth muscle cells in essential hypertension","volume":"595","author":"Cidad","year":"2017","journal-title":"J. Physiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"4162","DOI":"10.1016\/j.neuron.2022.09.029","article-title":"Subunit composition, molecular environment, and activation of native TRPC channels encoded by their interactomes","volume":"110","author":"Kollewe","year":"2022","journal-title":"Neuron"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.brainres.2006.02.087","article-title":"Immunohistochemical study on the distribution of TRPC channels in the rat hippocampus","volume":"1085","author":"Chung","year":"2006","journal-title":"Brain Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1002\/hipo.22081","article-title":"DAG-sensitive and Ca2+ permeable TRPC6 channels are expressed in dentate granule cells and interneurons in the hippocampal formation","volume":"23","author":"Nagy","year":"2013","journal-title":"Hippocampus"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"11011","DOI":"10.1073\/pnas.1309531110","article-title":"Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake","volume":"110","author":"Feng","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/s41398-022-02024-7","article-title":"Neuronal hyperexcitability in Alzheimer\u2019s disease: What are the drivers behind this aberrant phenotype?","volume":"12","author":"Matosin","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1111\/epi.17190","article-title":"Inhibition of TRPC3 channels by a novel pyrazole compound confers antiseizure effects","volume":"63","author":"Nagib","year":"2022","journal-title":"Epilepsia"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"6706","DOI":"10.1073\/pnas.0810599106","article-title":"A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice","volume":"106","author":"Becker","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Jeon, J., Bu, F., Sun, G., Tian, J.-B., Ting, S.-M., Li, J., Aronowski, J., Birnbaumer, L., Freichel, M., and Zhu, M.X. (2021). Contribution of TRPC channels in neuronal excitotoxicity associated with neurodegenerative disease and ischemic stroke. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.618663"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Phelan, K.D., Shwe, U.T., Wu, H., and Zheng, F. (2024). Investigating Contributions of Canonical Transient Receptor Potential Channel 3 to Hippocampal Hyperexcitability and Seizure-Induced Neuronal Cell Death. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25116260"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s10571-012-9875-6","article-title":"The reverse roles of transient receptor potential canonical channel-3 and-6 in neuronal death following pilocarpine-induced status epilepticus","volume":"33","author":"Kim","year":"2013","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1007\/s12035-014-8871-x","article-title":"Upregulation and diverse roles of TRPC3 and TRPC6 in synaptic reorganization of the mossy fiber pathway in temporal lobe epilepsy","volume":"52","author":"Zeng","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0896-6273(00)80838-7","article-title":"Activation of a TRPC3-dependent cation current through the neurotrophin BDNF","volume":"24","author":"Li","year":"1999","journal-title":"Neuron"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"5179","DOI":"10.1523\/JNEUROSCI.5499-06.2007","article-title":"TRPC3 channels are necessary for brain-derived neurotrophic factor to activate a nonselective cationic current and to induce dendritic spine formation","volume":"27","author":"Amaral","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2846","DOI":"10.1152\/jn.01140.2009","article-title":"Activity-dependent release of endogenous BDNF from mossy fibers evokes a TRPC3 current and Ca2+ elevations in CA3 pyramidal neurons","volume":"103","author":"Li","year":"2010","journal-title":"J. Neurophysiol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/11\/843\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:46:44Z","timestamp":1760032004000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/11\/843"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,4]]},"references-count":99,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["cells14110843"],"URL":"https:\/\/doi.org\/10.3390\/cells14110843","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,4]]}}}