Role of 5-HT1A and 5-HT7 Receptors in Memory Regulation and the Importance of Their Coexpression: A Systematic Review

Abstract

The 5-HT_1A and 5-HT₇ receptors play a key role in regulating cognitive processes and have been widely linked to the pathophysiology of depression, anxiety, and schizophrenia-disorders often associated with memory impairment. Recently, interest has grown in understanding how the coexpression of these receptors contributes to cognitive decline. This review explores the individual roles of 5-HT_1A and 5-HT₇ receptors, as well as their coexpression, in memory regulation. The heterodimerization of these receptors at both pre- and postsynaptic levels, along with their colocalization in serotonergic, glutamatergic, GABAergic, and dopaminergic neurons, adds to the complexity of this interaction and may help explain the paradoxical effects of selective serotonergic drugs (agonists and antagonists). These findings underscore the need for further research into the 5-HT_1A and 5-HT₇ receptor relationship in cognitive decline through diverse approaches, including targeted gene silencing, electrophysiology, and cell culture studies.

Keywords: agonist 5-HT1A; agonist 5-HT7; antagonist 5-HT1A; antagonist 5-HT7; coexpression; cognition; interplay; learning; memory; mice; rats.

Figure 1

Literature review of serotonergic drugs (5-HT_1A and 5-HT₇) and their coexpression associated with memory. The flow diagram illustrates the article selection process for this systematic review.

Figure 2

Activation of A class G proteins by 5-HT agonism in neuronal cells. (Left) 5-HT_1A activation by G_I/_O signaling by decreasing cAMP levels. (Right) 5HT₇ activation by G_S signaling by increasing cAMP formation and stimulating PLA2, Ca, MAPK, and PI3K. (Center) heterodimerization between 5HT_1A and 5HT₇ favoring G_S signaling and decreasing G_I/_O signaling. The terms and abbreviations used include the following: cAMP—cyclic adenosine monophosphate; PKA—protein kinase A; CREB—cAMP response element-binding; PLA2—phospholipase A2; MAPK—mitogen-activated protein kinases; PI3K—Phosphoinositide 3-kinase; PKB—protein kinase B; GSK-3β—Glycogen synthase kinase 3β. (Created in https://BioRender.com).

Figure 3

Hypothetical model illustrating the influence of oligomerization on cognitive impairment. (A) Under physiological conditions (top), a balance is observed in the postsynapse between the expression of 5-HT_1A/5-HT₇ heterodimers and 5-HT_1A homodimers, maintaining the postsynaptic release of neurotransmitters, including dopamine (DA), glutamate (Glu), gamma-aminobutyric acid (GABA), and serotonin (5-HT). (B) In cognitive impairment, an increase in 5-HT_1A homodimer expression compared to 5-HT_1A/5-HT₇ heterodimers may occur at the postsynaptic level, leading to a reduction in the exocytosis of DA, Glu, and 5-HT. The postsynaptic localization of the 5-HT₇ receptor (a, b, c, and d) indicates potential sites of action for serotonergic 5-HT₇ drugs, where site d may represent a key regulatory point in GABA release by interneurons.