Genetically encoded tools for Cell–Cell interactions underlying brain connectivity

Brain development and function depend on complex yet organized neural networks and efficient communication between the neurons that form these networks. To understand the role of neural networks and communication between neurons, it is important to visualize interactions between neurons. In this review, we provide a comprehensive overview of visualization tools for cell–cell interactions, especially among neurons. We first introduce tools based on fluorescent protein technology that directly visualize cell–cell interactions, categorized into three different mechanisms: split fluorescent protein (split FP), dimerization-dependent fluorescent protein (ddFP), and Förster resonance energy transfer (FRET). Each type offers distinct advantages in terms of temporal resolution, reversibility, and spatial specificity, making them suitable for different experimental contexts within neural networks. Next, we introduce tools that indirectly visualize cell–cell interactions, based on a reporter system. Finally, we present several tools based on other mechanisms. By systematically comparing the performance and applicability of each tool, we provide a strategic framework for selecting appropriate tools based on experimental goals, ranging from short-lived synaptic interactions to long-term network connectivity studies.