Cbln2 and Cbln4 are expressed in distinct medial habenula-interpeduncular projections and contribute to different behavioral outputs.

Cerebellins are important neurexin ligands that remain incompletely understood. Two critical questions in particular remain unanswered: do different cerebellins perform distinct functions, and do these functions act in the initial establishment of synapses or in rendering nascent synapses capable of normal synaptic transmission? Here we show that in mice, Cbln2 and Cbln4 are expressed in the medial habenula (MHb) nucleus in different types of neurons that project to distinct target neurons in the interpeduncular nucleus. Conditional genetic deletion of Cbln2 in the MHb impaired synaptic transmission at Cbln2⁺ synapses in the interpeduncular neurons within 3 wk, but decreased synapse numbers only after 3 mo, suggesting a functional, but not a structural, requirement for Cbln2 in synapses formed by Cbln2-expressing neurons. In contrast, genetic deletions of Cbln4 in the MHb had no major effect on synaptic transmission or synapse numbers in interpeduncular target neurons. Nevertheless, MHb ablation of both Cbln2 and Cbln4 significantly impaired behavioral responses in mice, but affected different types of behaviors. Specifically, Cbln2 MHb deletions decreased spatial learning, as measured in the water T-maze, whereas Cbln4 MHb deletions increased anxiety levels, as monitored in the open field test and elevated plus maze. Thus, Cbln2 and Cbln4 are expressed in distinct MHb neurons that contribute to different behaviors.

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