Interactions between ApCREB1a, ApCREB2, and ApC/EBP have been studied using conventional methods such as the yeast two-hybrid system. However, it is unclear whether these memory-related transcription factors actually interact in the native environment in neurons. To clarify this question, we have developed an Aplysia two-hybrid system and found, consistent with previous studies that ApCREB2 interacts with ApCREB1a and ApC/EBP, and that ApC/EBP forms homodimers. We have also found that ApCREB1a and ApC/EBP do not interact. Therefore, our study shows that formerly described interactions between the proteins actually occur in the Aplysia neurons and that interactions between these transcription factors are specific.