Cerebellin

Cerebellin-1 leads the way

The cerebellin family of proteins influences synapse formation and function. In this issue of PLOS Biology, Han and colleagues identify a new role for Cerebellin-1 in axon growth and guidance.

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

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.

Transsynaptic cerebellin 4-neogenin 1 signaling mediates LTP in the mouse dentate gyrus

Five decades ago, long-term potentiation (LTP) of synaptic transmission was discovered at entorhinal cortex↙dentate gyrus (EC↙DG) synapses, but the molecular determinants of EC↙DG LTP remain largely unknown. Here, we show that the presynaptic neurexin每ligand cerebellin-4 (Cbln4) is highly expressed in the entorhinal cortex and essential for LTP at EC↙DG synapses, but dispensable for basal synaptic transmission at these synapses. Cbln4, when bound to cell-surface neurexins, forms transcellular complexes by interacting with postsynaptic DCC (deleted in colorectal cancer) or neogenin-1. DCC and neogenin-1 act as netrin and repulsive guidance molecule-a (RGMa) receptors that mediate axon guidance in the developing brain, but their binding to Cbln4 raised the possibility that they might additionally function in the mature brain as postsynaptic receptors for presynaptic neurexin/Cbln4 complexes, and that as such receptors, DCC or neogenin-1 might mediate EC↙DG LTP that depends on Cbln4. Indeed, we observed that neogenin-1, but not DCC, is abundantly expressed in dentate gyrus granule cells, and that postsynaptic neogenin-1 deletions in dentate granule cells blocked EC↙DG LTP, but again did not affect basal synaptic transmission similar to the presynaptic Cbln4 deletions. Thus, binding of presynaptic Cbln4 to postsynaptic neogenin-1 renders EC↙DG synapses competent for LTP, but is not required for establishing these synapses or for otherwise enabling their function.

Towards an Understanding of Synapse Formation

Synapses are intercellular junctions specialized for fast, point-to-point information transfer from a presynaptic neuron to a postsynaptic cell. At a synapse, a presynaptic terminal secretes neurotransmitters via a canonical release machinery, while a postsynaptic specialization senses neurotransmitters via diverse receptors. Synaptic junctions are likely organized by trans-synaptic cell-adhesion molecules (CAMs) that bidirectionally orchestrate synapse formation, restructuring, and elimination. Many candidate synaptic CAMs were described, but which CAMs are central actors and which are bystanders remains unclear. Moreover, multiple genes encoding synaptic CAMs were linked to neuropsychiatric disorders, but the mechanisms involved are unresolved. Here, I propose that engagement of multifarious synaptic CAMs produces parallel trans-synaptic signals that mediate the establishment, organization, and plasticity of synapses, thereby controlling information processing by neural circuits. Among others, this hypothesis implies that synapse formation can be understood in terms of inter- and intracellular signaling, and that neuropsychiatric disorders involve an impairment in such signaling.

Plasma cerebellin levels in patients with central serous chorioretinopathy

Purpose: To evaluate levels of plasma cerebellin, cortisol, adrenaline and noradrenaline in patients with central serous chorioretinopathy (CSC).
Materials and methods: This prospective study included 30 patients diagnosed with acute CSC (Group 1) and a control group of 30 age-matched, healthy subjects without CSC (Group 2). Levels of plasma cerebellin, cortisol, adrenaline and noradrenaline were examined in blood samples taken after 8-12hours of fasting. A value of p<0.05 was considered statistically significant in the comparative analyses.
Results: The mean plasma cerebellin level was found to be 232.56㊣113.28 pg/ml in Group 1 and 174.07㊣82.04 pg/ml in Group 2 (p=0.02). Mean plasma cortisol was 13.19㊣3.87米g/ml in Group 1 and 9.55㊣2.92米g/ml in Group 2 (p<0.01). Mean plasma adrenaline was 60.62㊣26.67 pg/ml in Group 1 and 46.17㊣19.20 pg/ml in Group 2 (p=0.03). Mean plasma noradrenaline was 206.66㊣73.90 pg/ml in Group 1 and 149.96㊣51.36 pg/ml in Group 2 (p<0.01).
Conclusion: It can be concluded that increased cerebellin may have a role in the etiology of CSC by increasing catecholamine expression from the adrenal medulla and indirectly by increasing cortisol levels via a paracrine effect from the adrenal cortex.