The 5-HT6 receptor-associated signalling network in neuronal development – Sero6Dev

Cognitive symptoms accompanying neurodevelopmental pathologies such as schizophrenia or autism spectrum disorders are highly debilitating and current treatment options fail to alleviate them. Accordingly, there is an urgent need for new therapeutic approaches. It has become clear in the last few years that schizophrenia has a neuro-developmental origin. Specifically, cognitive symptoms might result from abnormalities in neuro-developmental processes such as migration, neurite outgrowth and synaptogenesis. Recent studies have demonstrated that the serotonin 5-HT6 receptor plays crucial roles in both the correct migration and positioning of neurons, and in neuronal differentiation and neurite growth. Interestingly, if some of the effects of the 5-HT6 receptor are mediated by its coupling to the canonical Gs pathway several lines of evidence show that most of the impact of the receptor on cognition and neuronal development involves additional signalling pathways that we identified thanks to a proteomics strategy. The receptor interacts with many proteins of the mammalian Target Of Rapamycin (mTOR) pathway, including mTOR itself. This pathway is over-activated in the prefrontal cortex in rodent models of schizophrenia, accounting for some of the cognitive deficits exhibited by these animals. The 5-HT6 receptor also interacts with Cyclin-dependent kinase (Cdk) 5 and several of its targets known to be involved in neurite growth and synaptogenesis. Further experiments showed that the 5-HT6 receptor controls neuronal migration and promotes neurite growth via a Cdk5-dependent mechanism.
Our preliminary data suggest that the 5-HT6 receptor also strongly influences dendritic tree complexity through an interaction with another protein partner, GPRIN1, and dendritic spine maturation via its interaction with WAVE1: treatment of primary hippocampal neurons with a 5-HT6 antagonist/inverse agonist favours dendritic spine maturation, while agonist stimulation of the receptor increases the proportion of immature dendritic spines in hippocampal neurons. However, the molecular basis underlying the feects of the receptor and its partners remain to be elucidated
Based on these findings, this proposal will have two general aims: on one hand, identifying in vivo new protein partners of the receptor which could be involved in its regulation of neurodevelopmental functions, and on the other hand studying in details the mechanisms by which the receptor and its previously identified partners, GPRIN1 and WAVE1, control dendritic tree complexity and dendritic spine maturation. To reach these two main goals, we will set five specific scientific tasks:
1) Identifying the interactome of the receptor in vivo in adult mice and at different neurodevelopmental stages
2) Characterizing the effect of the pharmacological modulation of the 5-HT6 receptor and of its genetic invalidation on neuronal architecture in cultured neurons and in vivo. We will focus on dendritic growth, neurite branching and the density and maturity of dendritic spines.
3) Characterizing the role of GPRIN1 under the control of the 5-HT6 receptor in neurite branching
4) Characterizing the role of WAVE1 under the control of the 5-HT6 receptor in dendritic spine maturation
5) Characterizing the role of new protein partners identified in step 1 on the control of neurodevelopmental processes by the 5-HT6 receptor
This program should shed light on the molecular basis of the control of the control of neurodevelopmental processes by the 5-HT6 receptor. Manipulating these pathways would be a valuable strategy for the treatment of cognitive deficits associated with neurodevelopmental diseases.