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Cerebellin-2 regulates a serotonergic dorsal raphe circuit that controls compulsive behaviors

Abstract

Cerebellin-1 (Cbln1) and cerebellin-2 (Cbln2) are secreted glycoproteins that are expressed in distinct subsets of neurons throughout the brain. Cbln1 and Cbln2 simultaneously bind to presynaptic neurexins and postsynaptic GluD1 and GluD2, thereby forming trans-synaptic adhesion complexes. Genetic associations link cerebellins, neurexins and GluD’s to neuropsychiatric disorders involving compulsive behaviors, such as Tourette syndrome, attention-deficit hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD). Extensive evidence implicates dysfunction of serotonergic signaling in these neuropsychiatric disorders. Here, we report that constitutive Cbln2 KO mice, but not Cbln1 KO mice, display robust compulsive behaviors, including stereotypic pattern running, marble burying, explosive jumping, and excessive nest building, and exhibit decreased brain serotonin levels. Strikingly, treatment of Cbln2 KO mice with the serotonin precursor 5-hydroxytryptophan or the serotonin reuptake-inhibitor fluoxetine alleviated compulsive behaviors. Conditional deletion of Cbln2 both from dorsal raphe neurons and from presynaptic neurons synapsing onto dorsal raphe neurons reproduced the compulsive behaviors of Cbln2 KO mice. Finally, injection of recombinant Cbln2 protein into the dorsal raphe of Cbln2 KO mice largely reversed their compulsive behaviors. Taken together, our results show that Cbln2 controls compulsive behaviors by regulating serotonergic circuits in the dorsal raphe.

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Fig. 1: Cbln2 KO mice, but not Cbln1 KO mice, exhibit compulsive jumping and nest building behaviors.
Fig. 2: Compulsive behaviors in Cbln2 KO mice are due to serotonergic dysfunction.
Fig. 3: Cbln2 is expressed both in serotonergic neurons in the dorsal raphe (DR) and in non-serotonergic neurons projecting to the DR.
Fig. 4: The constitutive Cbln2 KO increases glutamate receptor levels in the dorsal raphe and decreases the vGluT3 content of serotonergic nerve terminals in the anterior cingulate cortex without changing synapse densities.
Fig. 5: Cbln2 deletions induce explosive jumping of mice when Cbln2 is ablated both from DR neurons and from neurons projecting to the DR, while explosive jumping in Cbln2 KO mice can be rescued by stereotaxic injection of recombinant Cbln2 protein into the DR.

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Acknowledgements

This study was supported by a grant from the NIMH (MH052804 to TCS).

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Seigneur, E., Wang, J., Dai, J. et al. Cerebellin-2 regulates a serotonergic dorsal raphe circuit that controls compulsive behaviors. Mol Psychiatry 26, 7509–7521 (2021). https://doi.org/10.1038/s41380-021-01187-x

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