Cbln2, or Cerebellin-2, is a secreted glycoprotein that forms trans-synaptic adhesion complexes by binding to presynaptic neurexins and postsynaptic GluD1 and GluD2 receptors [1,2,4]. It plays a crucial role in regulating synaptic function, particularly in controlling the responses of AMPA-and NMDA-receptors in different neural circuits [1,2]. The Nrxn1-Cbln2-GluD1 and Nrxn3-Cbln2-GluD1 complexes have distinct effects on these receptors without affecting synapse formation [1,2].

In mice, constitutive Cbln2 KO mice display compulsive behaviors and decreased brain serotonin levels, indicating that Cbln2 controls compulsive behaviors by regulating serotonergic circuits in the dorsal raphe [4]. Conditional deletion of Cbln2 from dorsal raphe neurons and presynaptic neurons synapsing onto dorsal raphe neurons reproduced the compulsive behaviors [4]. In the medial habenula (MHb), conditional genetic deletion of Cbln2 impaired synaptic transmission at Cbln2+ synapses in the interpeduncular neurons within 3 weeks, and decreased synapse numbers only after 3 months, suggesting a functional requirement for Cbln2 in synapses formed by Cbln2-expressing neurons [3].

In conclusion, Cbln2 is essential for normal synaptic function and behavior regulation. Studies using KO and conditional KO mouse models have revealed its role in controlling compulsive behaviors and synaptic transmission in specific neural circuits. These findings contribute to understanding the pathogenesis of neuropsychiatric disorders related to compulsive behaviors [3,4].

References:

1. Dai, Jinye, Liakath-Ali, Kif, Golf, Samantha Rose, Südhof, Thomas C. 2022. Distinct neurexin-cerebellin complexes control AMPA- and NMDA-receptor responses in a circuit-dependent manner. In eLife, 11, . doi:10.7554/eLife.78649. https://pubmed.ncbi.nlm.nih.gov/36205393/

2. Südhof, Thomas C. 2023. Cerebellin-neurexin complexes instructing synapse properties. In Current opinion in neurobiology, 81, 102727. doi:10.1016/j.conb.2023.102727. https://pubmed.ncbi.nlm.nih.gov/37209532/

3. Seigneur, Erica, Polepalli, Jai S, Südhof, Thomas C. 2018. Cbln2 and Cbln4 are expressed in distinct medial habenula-interpeduncular projections and contribute to different behavioral outputs. In Proceedings of the National Academy of Sciences of the United States of America, 115, E10235-E10244. doi:10.1073/pnas.1811086115. https://pubmed.ncbi.nlm.nih.gov/30287486/

4. Seigneur, Erica, Wang, Jie, Dai, Jinye, Polepalli, Jai, Südhof, Thomas C. 2021. Cerebellin-2 regulates a serotonergic dorsal raphe circuit that controls compulsive behaviors. In Molecular psychiatry, 26, 7509-7521. doi:10.1038/s41380-021-01187-x. https://pubmed.ncbi.nlm.nih.gov/34158618/