Serotonin receptors as target in psychiatric and neurodegenerative disorders

Biog & Summary​

The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD).  5-HT1AR is palmitoylated and palmitoylation is essential for receptor functions. Here we found the palmitoylation of 5-HT1AR to be specifically reduced within the prefrontal cortex in the post-mortem samples from individuals with MDD that died by suicide. We also identified ZDHHC21 as the cognate palmitoylating enzyme and found that reduced ZDHHC21 expression in the prefrontal cortex of suicide subjects was connected to attenuated 5-HT1AR palmitoylation status. These findings were mirrored in several rodent models for depression-like behaviour. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation promising clinical strategy for the treatment of MDD.  In addition, we studied the role of the 5-HT7 serotonin receptor (5-HT7R) in tauopathies, which comprise a heterogeneous family of neurodegenerative diseases characterized by pathological accumulation of hyperphosphorylated Tau protein. We showed that the specific blockade of constitutive 5-HT7R activity in neurons that overexpressed human Tau[R406W] mutant associated with inherited forms of frontotemporal dementia prevented Tau hyperphosphorylation, aggregation, neurotoxicity, LTP deficits and memory impairments. Thus, 5-HT7R-mediated signalling emerged as a new, promising target for tauopathy treatments.