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Here, we show that PKC\u03b9\/\u03bb is persistently upregulated during maintenance in two mouse models: PKM\u03b6-conditional knockout mice, and double-knockout mice carrying both conditional deletion of PKC\u03b9\/\u03bb and constitutive loss of PKM\u03b6. Because PKC\u03b9\/\u03bb-gene excision is inducible in the double-knockout line, we could characterize the persistent increase of PKC\u03b9\/\u03bb in late-LTP prior to its deletion. To examine PKC\u03b9\/\u03bb function, we induced its deletion in the hippocampus. Whereas mutual compensation preserves LTP when either PKC\u03b9\/\u03bb or PKM\u03b6 alone is knocked out, double-knockout of both PKC\u03b9\/\u03bb and PKM\u03b6 eliminates late-LTP. Double-knockout also abolishes spatial long-term memory without affecting short-term memory. Thus, when PKM\u03b6 is absent, PKC\u03b9\/\u03bb persists to maintain hippocampal late-LTP and long-term memory.<\/jats:p>","DOI":"10.7554\/elife.110499","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T17:31:40Z","timestamp":1772472700000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.110499","source":"Crossref","is-referenced-by-count":0,"title":["PKM\u03b6-PKC\u03b9\/\u03bb double-knockout demonstrates atypical PKC is crucial for the persistence of hippocampal LTP and spatial memory"],"prefix":"10.7554","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1679-8980","authenticated-orcid":true,"given":"Panayiotis","family":"Tsokas","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01q1z8k08","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology and Pharmacology, The Robert F. 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