Interplay between serotonergic and L1-mediated signaling in regulation of neuronal morphology and functions under physiological and pathological conditions
Final Report Abstract
Morphological remodeling of dendritic spines is critically involved in memory formation and depends on adhesion molecules. Therefore, understanding the molecular mechanisms regulating neuronal morphology and synaptogenesis is a central point in studies investigating potential strategies for the treatment of neurological and psychiatric diseases. One of the signaling molecules critically involved in neurogenesis, neurite outgrowth, dendritic spine formation, and synaptic plasticity is serotonin, or 5-hydroxytryptamine (5- HT). Serotonin operates through the activation of a heterogeneous group of specific 5-HT receptors with different functions. One of these receptors, serotonin receptor 5-HT4 (5-HT4R), is known to regulate learning and memory, and is also involved in several neurological disorders, though the underlying mechanisms remain enigmatic. The main goal of the proposal was thus to uncover a signaling pathway involving the serotonin receptor 5-HT4 (5-HT4R) and its potential interaction partner – adhesion molecule L1. The L1 is known to be involved in neuronal migration, axonal development, growth cone formation, guidance of axons, and synaptic plasticity. L1 can also contribute to stress-related mood disorders and depression in humans, as well as animal models of depression. Similar to the 5-HT4R, the role of L1 in the regulation of neuronal morphology was demonstrated by L1-dependent cofilin phosphorylation and neurite outgrowth. In addition, L1-mediated ERK activation after the application of function-triggering antibodies to L1 may be important for the regulation of neuronal cell functions. However, the mechanisms underlying signaling transduction are not fully understood. Using FRET imaging, we demonstrated a physical interaction between 5-HT4R and L1 and found that 5-HT4R/L1 hetero-dimerization facilitates mitogen-activated protein kinase activation in a Gsdependent manner. We also found that 5-HT4R/L1-mediated signaling is involved in G13-dependent modulation of cofilin activity. In hippocampal neurons in vitro, the 5-HT4R/L1 pathway triggers maturation of dendritic spines. Thus, the 5-HT4R/L1 signaling module represents a previously unknown molecular pathway regulating synaptic remodeling.
Publications
- (2018) Cell Adhesion Molecule Close Homolog of L1 (CHL1) Guides the Regrowth of Regenerating Motor Axons and Regulates Synaptic Coverage of Motor Neurons. Front Mol Neurosci 11:174
Guseva D, Jakovcevski I, Irintchev A, Leshchyns'ka I, Sytnyk V, Ponimaskin E, Schachner M
(See online at https://doi.org/10.3389/fnmol.2018.00174) - (2020) Pro-Kinetic Actions of Luminally-Acting 5-HT4 Receptor Agonists. Neurogastroenterol Motil.
Konen JR, Haag MM, Guseva D, Hurd M, Linton AA, Lavoie B, Kerrigan CB, Joyce E, Bischoff SC, Swann S, Griffin L, Matsukawa J, Falk M, Gibson TS, Hennig FW, Wykosky J, Mawe GM
(See online at https://doi.org/10.1111/nmo.14026) - Neuronal branching of sensory neurons is associated with BDNF-positive eosinophils in atopic dermatitis. Clin Exp Allergy 50(5): 577–584
Guseva D, Rüdrich U, Kotnik N, Gehring M, Patsinakidis N, Agelopoulos K, Ständer S, Homey B, Kapp A, Gibbs BF, Ponimaskin E, Raap U
(See online at https://doi.org/10.1111/cea.13560)
