EFFECT OF THE 5HT1A RECEPTOR AGONIST NLX-101 AND ERK SIGNALLING ON CORTICAL NEURONAL GROWTH

Serotonin (5-HT) has a multitude of functions in the central nervous system and, in addition to modulating neuronal function, has also been reported to act as a morphogen during development and affect neurite extension. However, the precise molecular mechanisms that underlie the effect of 5-HT on neurite extension are not well characterised and the interpretation of studies in the intact nervous system is challenging due to the complexity of cellular interactions, which makes it difficult to differentiate between direct and indirect effects. In order to address whether activation of 5HT1A receptors expressed on cortical neurons directly affects neurite extension, we have studied the effect of the highly selective 5HT1A receptor agonist NLX-101 on neurite extension and the morphology of ‘pyramidal-like’ neurons in primary cultures of mouse cortical neurons. Single cell tracings revealed a concentration-dependent subtle, but significant increase in neurite extension. Interestingly, application of SCH-772984 to block the extracellular signal-regulated kinase (ERK) signalling pathway did not appear to prevent the growth promoting effect of 5HT1A receptor activation. Instead, SCH-772984 mimicked the effect of 5HT1A receptor activation, and even on its own promoted neurite extension in primary cortical neurons. Thus, we suggest that 5HT1A receptor effects on neurite growth may not be mediated via the activation of ERK as suggested based on work in non-neuronal cells and immortalised hippocampal HN2-5 cells (Rojas PS and Fiedler JL, 2016, Front. Cell. Neurosci. 10:272. doi: 10.3389/fncel.2016.00272), but via some alternative signalling pathway, likely related to its effect on intracellular cAMP concentrations.