http://kb.mozillazine.org/Application_not_responding

1. Exit Thunderbird.
2. Find your profile folder.
3. Open the folder containing your stored messages.
4. Select the *.msf files and delete them.
5. Restart Thunderbird.
6. Wait for Thunderbird to recreate the mail summary file(s).

For example, if you are using the Global Inbox, this would be the Local Folders folder inside the Mail folder. Otherwise, it may be a folder named after the mail server inside the Mail or ImapMail folder. For example, “pop.gmail.com” if you're using gmail.

http://kb.mozillazine.org/Compacting_folders

Tools → Account Settings → Server Settings → “When I delete a message”

In TB, select a top-level account on the left, then:

File → Compact Folders

Account Settings → Server Settings → Clean up (“Expunge”) Inbox on Exit

Preferences → Advanced → Network & Disk Space → “Compact folders when it will save over X MB”

• The TB UI may 'hang' noticeably during expunge operations
• Enable automatic expunging of all folders
  • Smaller numbers will cause TB to compact folders more often
  • Larger numbers will cause TB to compact folders less often
  • 20MB is the default
  • 1MB is often recommended

Preferences → Advanced → General → Advanced Configuration → Enable Global Search and Indexer

Account Settings → (each account) → Junk Settings

Preferences → Security → Junk

Reset Training Data can fix some problems and is global affecting all accounts.