Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction–induced memory enhancement

Abstract

Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan—a precursor amino acid for serotonin biosynthesis in the brain—and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake.

Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis

“…Although we currently have no evidence that citrate supplementation can induce lifespan extension in mice, the improved metabolic health and cognitive function observed in citrate-treated mice are often linked to pro-longevity interventions in animal studies. For example, DR has been shown to improve metabolic health or cognitive performance in both young and aged animals (Dommerholt et al, 2018;Sohal et al, 1994;Teng et al, 2019). The DR mimetic, rapamycin (TOR inhibitor), has been shown not only to induce lifespan extension, but also, age-independently, to improve cognitive performance and metabolic health in mice (Neff et al, 2013).…”

“…shown to couple with altered memory performance in animals (Teng et al, 2019). We performed the Golgi-Cox impregnation staining method, and reconstructed dendritic profiles of dentate gyrus (DG) granule cells in the mouse hippocampus, using Neurolucida software.…”

“…A similar approach to limiting cellular energy is achieved through dietary restriction (DR, 20%-40% reduction in food intake), a well-documented regimen that has been established as the most effective intervention for prolonging healthy lifespan across multiple species (Lin et al, 2000;Mattison et al, 2017;Tatar et al, 2014;Weindruch et al, 1986). Studies investigating the underlying mechanism of DR have identified signaling pathways involving nutrient-sensing and metabolism, such as sirtuins (Sir), AMP-activated protein kinase (AMPK), target of rapamycin (TOR), and downstream ketogenesis pathways (Kaeberlein et al, 2005;Lin et al, 2000;Newman et al, 2017;Roberts et al, 2017;Stenesen et al, 2013;Teng et al, 2019). Interventions acting on these targets often result in improved metabolic health and lifespan extension (Madeo et al, 2019).…”

Blockade of Serotonin 5-HT6 Receptor Constitutive Activity Alleviates Cognitive Deficits in a Preclinical Model of Neurofibromatosis Type 1

“…In addition to its coupling to Gs protein, the 5-HT 6 receptor also engages mTOR signaling to compromise cognition in neurodevelopmental models of schizophrenia [ 20 ] and preclinical models of cannabis abuse during adolescence [ 22 ] and neuropathic pain [ 23 ]. Conversely, reduced 5-HT 6 receptor-operated mTOR signaling has been involved in memory enhancement elicited by dietary restriction in the mouse [ 24 ]. Collectively, these findings suggest that blocking the 5-HT 6 receptor-mTOR pathway might be a promising strategy to alleviate cognitive deficits associated with neuropsychiatric disorders of different etiologies [ 20 , 22 , 25 , 26 , 27 ].…”

HTR6 and SSTR3 targeting to primary cilia

“…HTR6, also known as 5-HT 6 or 5-HTR 6 , is expressed in brain, with highest levels in basal ganglia and cerebral cortex [15,16]. It is involved in many pathophysiological processes including, among others, learning, memory, reward-motivated behaviors, depression, anxiety, drug addiction, schizophrenia, epilepsy, eating disorders and Alzheimer's disease (AD) [15,17]. Unlike other serotonin receptors, HTR6 robustly localizes to cilia, both in vivo and in vitro, where it is often used as a ciliary membrane marker or ciliary targeting tool [18][19][20][21][22].…”