I know that the Spellplague was the Forgotten Realms transition from D&D 3.5e to D&D 4e, and the Second Sundering was the transition from D&D 4e to D&D 5e, but I'm curious about other lore events marking earlier transitions. So:
What major events in the Forgotten Realms marked transitions from one edition of D&D to another?
Specific events I imagine might have been transitions (but can't find any evidence of) include Karsus's Folly and the Time of Troubles.
You've found them all.
The Forgotten Realms was first published for AD&D 1st edition. When 2nd edition came out, the change in spells and available classes was explained through the Godswar aka The Time of Troubles.
The introduction of D&D 3e was exceptional in that there was no overarching, global in-setting event introduced to explain the rules changes. Oddly, the adventure Die Vecna Die! was intended to explain the rules changes (for all D&D settings), but its events were never made FR canon. WotC just proceeded with the 3e rules and setting changes without adding any corresponding historical events. The 3e change is thus “silent” in FR's historical record.
Karsus's Folly was made global setting canon with 3e as a historical detail that further developed the history of Netheril and explained some changes local to the Anauroch and some new game elements, but it wasn't the same kind of global upheaval—it was more of a retcon slipped in as undisruptively as possible.1
The Spellplague (and about a century) explained the shift from D&D 3.x to 4e, and the Second Sundering did the same for the transition to 5e.
Given that the question is tying game mechanics with in-game events, I would like to offer an answer that follows the in-game history of the setting, and not the real-world history. The in-game history was gradually reconstructed with the past (such as the Arcane Age) written after the "present", which leads to interpretations as in the answer by SevenSidedDie, some points of whom I disagree with. For example, there are data supporting that Karsus's Folly was indeed FR canon during the 2e.
The Arcane Age line of products are something like a mini-edition, it is AD&D 2nd edition with various modifications (like the absence of Vancian spellcasting, which had been a staple of D&D from the first published game). After this event, the game mechanics change to those of AD&D 1st edition. Quoting from the Netheril: Empire of Magic boxed set (page 32-33, emphasis mine):
After the death of Mystryl, ... specialty priests ceased to exist; priests became clerics, ... Paladins received spells from the cleric spell list; rangers received spells from the druid spell list (from the original AD&D game, or simply use the spheres available for druids in the Player’s Handbook).
Same thing is made even more explicit in the campaign expansion adventure, How the Mighty are Fallen (HtMaF). Quoting (pages 53-54, again emphasis mine):
For DMs who desire to be historically accurate, game play reverts to strict original AD&D rules (not 2nd Edition). This means that clerics and druids are two separate classes, as are mages and illusionists. Specialty priests and specialist wizards no longer exist.
... assassins were hired from the ranks of the thieves guilds .... Soon, the assassins had a guild of their own. ... The reformation of the bards ... nearly destroyed the profession. Bards left their dependence on wizard spells behind, instead opting to learn a bit about everything. They became fighters (until 5th level or so) and then became thieves, remaining so until they had achieved at least 5th level in their new class. Finally, they left thievery behind to study with the druids, gaining druid spells as they advanced.
Also known as the Avatar Crisis, or Godswar, this event was used to explain the transition from AD&D 1e to 2e. For example, the complete removal of the 1e assassin class (whose introduction is alluded to in the above quote from HtMaF) from the game was tied to the death of deity Bhaal, whose portfolio was murder. Much like how the How the Mighty are Fallen is the adventure allowing players to experience the transition, a trilogy of modules, called the Avatar Trilogy (Shadowdale, Tantras, Waterdeep), allows players to do the same for this transition.
The third edition Player's Handbook was published in 2000. There were still 2e materials being published in that year, and amongst them is the FR campaign expansion Cloak and Dagger, which covers the timeline between 1368 to 1370 DR in its chapter 2; and mentions a few things for the "future", 1371 DR onwards. When the 3e FR Campaign Setting was published in 2001, it stated 1372 DR as its current year (page 78).
This transition is smooth in the FR. However, 2e to 3e transition is often associated with the adventure module Die Vecna Die!, which takes place in Greyhawk, Ravenloft and Planescape campaign settings, the last of which is really a metasetting that includes FR. That adventure ends with (page 151):
Some Outer Planes drift off and are forever lost, others collide and merge, while at least one Inner Plane runs "aground" on a distant world of the Prime. Moreover, the very nature of the Prime Material Plane itself is altered. ... New realms, both near and far, are revealed, and realms never previously imagined make themselves known. Entities long thought lost emerge once more, while other creatures, both great and small, are inexplicably eradicated. Some common spells begin to work differently. The changes do not occur immediately, but instead are revealed during the subsequent months. However, one thing remains clear: Nothing will ever be the same again.
With the murder of Mystra, the Weave of magic unravels. Cyric's madness as well as energies from the Far Realm completely poison the magic. Various calamities take place over some years, partly because various geographies on the planets Abeir and Toril swap places. 4e products start about a hundred years of in-game time after.
The planets Abeir and Toril start to separate. Mystra and many other deities return. In 1489 DR, Ao declares the end of the Era of Upheaval. Players can experience parts of this story with the Living Forgotten Realms adventure The End and the Beginning.
Karsus' Folly is not an edition-changing event. It was published in adnd-2e for the Arcane Age series (where it was encouraged to use time-traveling PC parties, or to make up your own netherese characters. It marked a major change in the world, but it was a change from the Arcane Age itself into the AD&D rules.
From the adventure How the Mighty are Fallen
The party is tasked with gathering the materials for the Avatar spell. Including the pituitary gland of the Tarrasque. Later on, during a raid on a Lich's castle, magic just stops working, as Karsus casts his spell.
The game then instructs players to switch from the point-based spellcasting of Arcane Age Netheril back into the AD&D vancian magic system.
If you look at a "minor" event to mark the transition from AD&D 2e into dnd-3.5 you could use The return of the City of Shade (and the Release of the Phaerimm from the Sharn Wall) as such marker.
