Mechanisms of input and output synaptic specificity: finding partners, building synapses, and fine-tuning communication

•Cell adhesion systems are critical determinants of synaptic specificity.•Neuroligins and FGFs contribute to the balance of inhibitory to excitatory synapses.•Synaptic plasticity mechanisms can differ for different synaptic inputs and outputs.•New tools are advancing our molecular understanding of synaptic specificity.

For most neurons to function properly, they need to develop synaptic specificity. This requires finding specific partner neurons, building the correct types of synapses, and fine-tuning these synapses in response to neural activity. Synaptic specificity is common at both a neuron's input and output synapses, whereby unique synapses are built depending on the partnering neuron. Neuroscientists have long appreciated the remarkable specificity of neural circuits but identifying molecular mechanisms mediating synaptic specificity has only recently accelerated. Here, we focus on recent progress in understanding input and output synaptic specificity in the mammalian brain. We review newly identified circuit examples for both and the latest research identifying molecular mediators including Kirrel3, FGFs, and DGLα. Lastly, we expect the pace of research on input and output specificity to continue to accelerate with the advent of new technologies in genomics, microscopy, and proteomics.