Cerebellin

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-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.

Purpose:Preeclampsia is a form of hypertensive disorders of pregnancy and defined as the presence of new-onset hypertension and proteinuria or other end organ damage occurring after 20-week gestation. Preeclampsia can be a destructive process that can cause maternal and infant mortality. The exact etiopathogenesis of preeclampsia is still undefined. We aimed to compare serum amphiregulin and cerebellin-1 levels of severe preeclampsia patients with healthy pregnant women and healthy control subjects.Materials and methods:A total of 88 women were enrolled in this study. Patients diagnosed with severe preeclampsia were group 1 (n= 28), healthy non-pregnant normotensive women group 2 (n= 30), and healthy pregnant women group 3 (n= 30). The participants in each group were matched for age. Pregnant women in groups 1 and 3 were also matched for gestational age. Serum amphiregulin and cerebellin-1 levels were measured using ELISA.Results:Serum amphiregulin levels were 3413 ± 1.38 ng/ml (1748-7739), 8510 ± 7213 ng/ml (2019-24,000), and 6580 ± 5360 ng/ml (2484-24,000) in preeclampsia patients, controls and healthy pregnant women, respectively. Amphiregulin levels were significantly lower in preeclampsia patients than healthy pregnant women (p=.008) and controls (p= .015). Amphiregulin levels were similar between healthy controls and healthy pregnant women (p= 1.00). Cerebellin-1 levels were 222.039 ± 92.681 pg/ml (138,580-557,757) in preeclamptic patients, 537.043 ± 525.117 pg/ml (150,432-1,600,000) in controls and 415.091 ± 436.580 pg/ml (137,284-1,600,000) in healthy pregnant women. Cerebellin-1 levels were similar among groups (p= .272). Serum amphiregulin and cerebellin-1 levels were significantly and positively correlated with each other in preeclampsia patients (r= 0.693,p< .001), controls (r= 0.882,p< .001), and healthy pregnant women (r= 0.591,p= .001). Serum level of amphiregulin ≤3590 pg/ml had a sensitivity of 67.9% and specificity of 63.3% in the diagnosis of preeclampsia (AUC: 0.751;p= .001).Conclusions:Serum amphiregulin decreases in severe preeclampsia patients.

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.