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The mechanism of IPC has mainly been studied in rodent stroke models where gray matter (GM) constitutes about 85% of the cerebrum. In humans, white matter (WM) is 50% of cerebral volume and is a critical component of stroke damage. We developed a novel CNS WM IPC model using the mouse optic nerve (MON) and identified the involved immune signaling pathways. Here we tested the hypothesis that microglia are necessary for WM IPC. Microglia were depleted by treatment with the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622. MONs were exposed to transient ischemia in vivo, acutely isolated 72\u2009h later, and subjected to oxygen\u2013glucose deprivation (OGD) to simulate a severe ischemic injury (i.e., stroke). Functional and structural axonal recovery was assessed by recording compound action potentials (CAPs) and by microscopy using quantitative stereology. Microglia depletion eliminated IPC\u2010mediated protection. In control mice, CAP recovery was improved in preconditioned MONs compared with non\u2010preconditioned MONs, however, in PLX5622\u2010treated mice, we observed no difference in CAP recovery between preconditioned and non\u2010preconditioned MONs. Microgliadepletion also abolished IPC protective effects on axonal integrity and survival of mature (APC<jats:sup>+<\/jats:sup>) oligodendrocytes after OGD. IPC\u2010mediated protection was independent of retinal injury suggesting it results from mechanistic processes intrinsic to ischemia\u2010exposed WM. We conclude that preconditioned microglia are critical for IPC in WM. The \u201cpreconditioned microglia\u201d phenotype might protect against other CNS pathologies and is a neurotherapeutic horizon worth exploring.<\/jats:p>","DOI":"10.1002\/glia.24132","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T19:45:41Z","timestamp":1640288741000},"page":"661-674","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Microglial depletion abolishes ischemic preconditioning in white matter"],"prefix":"10.1002","volume":"70","author":[{"given":"Margaret A.","family":"Hamner","sequence":"first","affiliation":[{"name":"Department of Neurology School of Medicine, University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3864-9449","authenticated-orcid":false,"given":"Ashley","family":"McDonough","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine, University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davin C.","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine, University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levi J.","family":"Todd","sequence":"additional","affiliation":[{"name":"Department of Biological Structure School of Medicine, University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"German","family":"Rojas","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine, University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibylle","family":"Hodecker","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine, University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher B.","family":"Ransom","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine, University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Reh","sequence":"additional","affiliation":[{"name":"Department of Biological Structure School of Medicine, University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce R.","family":"Ransom","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine, University of Washington  Seattle Washington USA"},{"name":"Neuroscience Department City University of Hong Kong  Kowloon Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6080-9758","authenticated-orcid":false,"given":"Jonathan R.","family":"Weinstein","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine, University of Washington  Seattle Washington USA"},{"name":"Department of Neurological Surgery School of Medicine, University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2011.6"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5137-07.2008"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2015.02.005"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-020-01010-8"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1715"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2012.06691.x"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0122912"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.02.040"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12832"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0324-18.2018"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-006-9015-5"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1927"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12262"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2544-15.2015"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1997"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0584-17.2017"},{"key":"e_1_2_9_18_1","volume-title":"Unbiased stereology","author":"Howard C. 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