Serotonin, a phylogenetically ancient molecule that predates the evolution of the nervous system, was likely co-opted to function as a neurotransmitter. Serotonin retains ‘pre-nervous’ trophic-factor actions influencing development and growth, while exerting pleiotropic neurotransmitter effects on diverse brain functions and behavior. Serotonin is speculated to exert antioxidant-like actions; however, its influence on the energy producing organelle, mitochondria, and on a neuron’s stress buffering capacity remains poorly understood.

The webinar will discuss evidence that serotonin, via the serotonin2A receptor, enhances mitochondrial biogenesis in rodent cortical neurons, increases mitochondrial function, respiratory capacity, and ATP generation. These intriguing effects arise via recruitment of master modulators of mitochondrial biogenesis, the sirtuin SIRT1, and the transcriptional coactivator PGC-1α, that are strongly implicated in metabolic control and longevity. Serotonin infusion or chemogenetic activation of endogenous serotonin release increases neocortical mitochondrial mass and function. The serotonin-mediated increase in respiration and ATP production is not simply a consequence of greater mitochondrial mass, but also reflects improved OxPhos efficiency per mitochondrion.

The webinar will also discuss research that identifies the serotonin2A receptor-SIRT1-PGC-1α axis as a putative target to enhance neuronal mitochondrial function. Finally, the talk will place into context the contribution of mitochondrial modulation to the effects of serotonin on mood regulation, neuroplasticity, and senescence.

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