I am not terribly familiar with neuroscience, so you will have to forgive me for asking, but why would this be particularly troubling? Is the concern that surrounding neurons would neglect to "hook up" with the synthetic one, once they got used to nothing being there?
None of this is overly important per-se. Your brain doesn't have a specific pattern of arrangements that must be just so to make a human. But as you start changing these little details, the changes will eventually bubble up to create a different "you".
How much different is hard to say, maybe not even enough to be noticeable. This is firmly in "theoretical" territory. But considering how drastically people can change from relatively small strokes, I would hazard that there isn't a huge amount of deviance allowed.
Perhaps it's possible if you can do it finely enough that only single neurons are changing, allowing time to resynapse (or artificially recreating those connections?). Not sure.
Either way though you are going to create an intelligence that will likely be unable to relate to biological people, and biological people will probably have just as much difficulty relating to it. I wouldn't be surprised if an uploaded person was viewed as some sort of psychopath after the procedure, no matter how perfect the procedure was. (And considering how biological people will probably treat it, it would probably be very justified in thinking the same of them)
As long as the individual is happy with the results, no matter how changed they become, that is probably the best we could hope to shoot for.