Cooperative interaction between serotonergic signalling and extracellular matrix in regulation of synaptic plasticity under physiological and pathological conditions

点击翻译按钮获取中文摘要

Long-lasting alterations in the efficacy of synaptic transmission (synaptic plasticity) are regarded as a central mechanism for learning and memory. Synaptic plasticity goes along with molecular and morphological changes in the pre- and post-synapse and results in the rewiring of the neural network on a larger scale, which plays a key role in a wide range of neurological and cognitive disorders. We have previously demonstrated that the serotonin receptor 7 (5-HT7R) possesses pronounced morphogenic properties. Receptor-mediated activation of the heterotrimeric G12 protein results in a selective activation of small GTPase Cdc42, which in turn leads to prominent changes in cellular morphology, including neurite outgrowth and synaptogenesis. Structural remodeling and synaptic plasticity depend not only on morphogenic signaling in neurons, but also on the reorganization of the surrounding extracellular matrix (ECM). The central component of the brain’s ECM is hyaluronan (HA), which forms the backbone of perineuronal nets and influences both structural and functional aspects of plasticity. The main receptor for HA is the transmembrane protein CD44.We have also identified a functional interplay between serotonergic signaling and ECM by uncovering a novel signaling pathway involving the 5-HT7R, the CD44, the matrix metalloproteinase-9 (MMP-9), and the small GTPase Cdc42. The underlying molecular machinery involves 5-HT7R-mediated activation of MMP-9, which leads to CD44 cleavage followed by Cdc42 activation. We also highlighted physical interaction between 5-HT7R and CD44. However, mechanisms regulating formation and stability of the 5-HT7R/CD44 complex as well as functional impact of this interaction in neurons are still not known. One important goal of the present proposal is thus to understand the molecular mechanisms regulating the formation of 5-HT7R/CD44 complexes and to elucidate their functional consequences in neurons, including modulation of intracellular signaling pathways, structural remodeling, and synaptic plasticity.In our preliminary experiments we demonstrated that CD44 is post-translationally modified by palmitoylation in the brain. Furthermore, we identified putative palmitoylation site within the C-terminal domain of CD44. Therefore, our second goal is to define mechanisms regulating CD44 palmitoylation on a molecular level and to analyze the involvement of CD44 palmitoylation in the modulation of the 5-HT7R/CD44 signaling in neurons. Finally, we will investigate the impact of the 5-HT7R/CD44 signaling and CD44 palmitoylation in vivo under physiological and pathological conditions. The latter also implies verification of the 5-HT7R/CD44 complexes as a potential therapeutic target for the treatment of depressive disorders.