Cbln4, or Cerebellin-4, is a secreted adaptor protein. It is part of the cerebellin family (Cbln1-4) and is crucial for synapse-related functions. Cbln4 connects presynaptic neurexins to postsynaptic ligands such as DCC (deleted in colorectal cancer) and Neogenin-1, participating in trans-synaptic signaling pathways that are essential for certain synaptic properties but not for synapse formation [1,2].

In KO mouse models, presynaptic deletion of Cbln4 in the entorhinal cortex demonstrated its requirement for long-term potentiation (LTP) at entorhinal cortex→dentate gyrus (EC→DG) synapses, while basal synaptic transmission remained unaffected [2]. In the medial habenula (MHb), genetic deletion 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 an in vitro AD model, upregulation of Cbln4 relieved Aβ1-42-induced cell apoptosis, inflammation, oxidative stress, and endoplasmic reticulum stress [4].

In summary, Cbln4 plays a significant role in synapse-related functions, particularly in regulating LTP at specific synapses and contributing to anxiety-related behaviors. Studies using Cbln4 KO mouse models have provided insights into its functions in the context of synaptic plasticity and certain behavioral outputs, as well as its potential role in neurodegenerative diseases like Alzheimer's disease.