Cbln4, a member of the cerebellin family, is a secreted adaptor protein. It plays crucial roles in synapse-related functions. Cbln4 forms transcellular complexes by interacting with presynaptic neurexins and postsynaptic DCC or neogenin-1, and is involved in pathways regulating synapse properties. Its overall biological importance lies in its contribution to synaptic plasticity and the normal functioning of the nervous system. Genetic models, such as knockout mice, have been valuable in studying its functions [1,2].

In knockout mouse models, presynaptic deletion of Cbln4 in the entorhinal cortex was found to be essential for long-term potentiation (LTP) at entorhinal cortex→dentate gyrus (EC→DG) synapses, yet dispensable for basal synaptic transmission at these synapses [2]. In the medial habenula (MHb), genetic deletions of Cbln4 had no major effect on synaptic transmission or synapse numbers in interpeduncular target neurons, but Cbln4 MHb deletions increased anxiety levels in mice [3]. In the retina, conditional knockout of Cbln4 led to a small deficit in directional tuning among ventral-preferring DSGCs, suggesting its role in the development of direction-selective (DS) circuits [4].

In conclusion, Cbln4 is essential for LTP at specific synapses, contributes to the regulation of anxiety-related behaviors, and plays a role in the development of DS circuits in the retina. Studies using Cbln4 KO mouse models have provided important insights into its functions in these biological processes and disease-relevant behaviors, such as anxiety-related phenotypes.