A 500 Internal Server Error related to `pg_replication_slots` in PostgreSQL often indicates issues with replication configuration or slot management. Common causes include inactive replication slots consuming resources, slots preventing WAL file deletion, or network connectivity problems between the primary and replica servers. Solutions involve identifying and deleting inactive slots using `pg_drop_replication_slot`, ensuring the replica server is properly connected and replicating, and reviewing PostgreSQL logs for detailed error messages. Regular monitoring of replication slots is essential for preventing future errors.