Interaction between CHL1 and serotonin receptor 2c regulates signal transduction and behavior in mice

Abstract

The serotonergic system plays important roles in multiple functions of the nervous system and its malfunctioning leads to neurological and psychiatric disorders. Here, we show that the cell adhesion molecule close homolog of L1 (CHL1), which has been linked to mental disorders, binds to a peptide stretch in the third intracellular loop of the serotonin 2c (5-HT2c) receptor through its intracellular domain. Moreover, we provide evidence that CHL1 deficiency in mice leads to 5-HT2c-receptor-related reduction in locomotor activity and reactivity to novelty, and that CHL1 regulates signaling pathways triggered by constitutively active isoforms of the 5-HT2c receptor. Furthermore, we found that the 5-HT2c receptor and CHL1 colocalize in striatal and hippocampal GABAergic neurons, and that 5-HT2c receptor phosphorylation and its association with phosphatase and tensin homolog (PTEN) and β-arrestin 2 is regulated by CHL1. Our results demonstrate that CHL1 regulates signal transduction pathways through constitutively active 5-HT2c receptor isoforms, thereby altering 5-HT2c receptor functions and implicating CHL1 as a new modulator of the serotonergic system.

Chronic mild stress impairs latent inhibition and induces region-specific neural activation in CHL1-deficient mice, a mouse model of schizophrenia

“…Although some neuronal cell adhesion molecules of the immunoglobulin superfamily, such as NCAM and L1, are considered important mediators of the effects of stress on the brain [104, 105], to date nothing is known of the interaction between stress and CHL1 expression. It is possible that the effect is indirect, for example through effects on interneurons [106] or through effects on serotonergic circuits [107]. …”

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

“…5-HT2CR as many others have a complex pattern of interations with multiple GIPs (GPCR interacting proteins, see e.g. Becamel et al 2001;2002;Parker et al 2003;Gavarini et al 2006;Labasque et al 2008;Maillet et al 2008;Kleene et al 2015). Finally, 5-HT2CR antagonists (or at least inverse agonists), may help in controlling involuntary movements / muscle spasms that result from a marked increase in constitutive 5-HT2CR activity in spinal cord injury patients.…”

Increased temporal discounting after chronic stress in CHL1-deficient mice is reversed by 5-HT2C agonist Ro 60-0175

“…Of particular interest is a recently identified interaction between CHL1 and the serotonin receptor 5-HT2C (Kleene et al, 2015). Abnormal behaviors (such as a reduced reactivity to novelty) in CHL1-deficient mice are thought to result from abnormal signaling through constitutively active 5-HT2C receptor isoforms (Kleene et al, 2015), and can be rescued with 5-HT2C antagonists, which increase DA neuronal activity and striatal DA levels (Alex et al, 2005).…”

“…Abnormal behaviors (such as a reduced reactivity to novelty) in CHL1-deficient mice are thought to result from abnormal signaling through constitutively active 5-HT2C receptor isoforms (Kleene et al, 2015), and can be rescued with 5-HT2C antagonists, which increase DA neuronal activity and striatal DA levels (Alex et al, 2005). Stress increases sensitivity of 5-HT2C receptors in the striatum (Strong et al, 2011), and alters expression of other serotonin receptors as well (Chang et al, 2016).…”

“…Here we assessed temporal discounting in CHL1-deficient mice under basal and chronic stress conditions, and we investigated the neural circuits underlying this behavior using measures of neuronal activation (cFos positive cell counts) and pharmacological approaches. We have used Ro 60-0175, an agonist for 5-HT2C receptors, specifically because a biochemical interaction was demonstrated between the CHL1 protein and the 5-HT2C receptor (Kleene et al, 2015). …”