The history of the main cast is very interesting actually. All three of them are
officially main.
Mrs. Puff and Pearl have always been main characters, but that's not the case for Plankton, Karen, or Gary. The distinction between main and non-main is very important to the crew of an animated show, because the model sheets need to designate who's main and who isn't. The voice actors also get different payments based on how they're billed (main vs. guest). It's not something fans can just decide for themselves... the main cast was the decision of the crew.
Ever since season one, Mrs. Puff and Pearl have been on the main character model sheet. Gary, Plankton, and Karen weren't on the season one sheet, and were billed as recurring characters for that season. Gary was promoted in season two, followed by Plankton and Karen in season four. There are currently ten main characters and that's stayed the same ever since. Appearance count doesn't change how they're billed on the model sheets, and Vincent Waller
has said: "I don't keep a running tally of how often we include characters in any given season."
(As an added note, Nickelodeon more or less
forced Stephen Hillenburg to add Mrs. Puff to the show in 1997, because they refused to air it if there wasn't a teacher as a main character. If she wasn't main, the show wouldn't have gotten picked up in the first place. As for Plankton, Nickelodeon wanted him to be a one-off guest star until Doug Lawrence started writing new ideas for him, hoping to prove that Plankton had potential for more than one story.)