Memory Disorders Related to Hippocampal Function: The Interest of 5-HT4Rs Targeting

Abstract

The hippocampus has long been considered as a key structure for memory processes. Multilevel alterations of hippocampal function have been identified as a common denominator of memory impairments in a number of psychiatric and neurodegenerative diseases. For many years, the glutamatergic and cholinergic systems have been the main targets of therapeutic treatments against these symptoms. However, the high rate of drug development failures has left memory impairments on the sideline of current therapeutic strategies. This underscores the urgent need to focus on new therapeutic targets for memory disorders, such as type 4 serotonin receptors (5-HT4Rs). Ever since the discovery of their expression in the hippocampus, 5-HT4Rs have gained growing interest for potential use in the treatment of learning and memory impairments. To date, much of the researched information gathered by scientists from both animal models and humans converge on pro-mnesic and anti-amnesic properties of 5-HT4Rs activation, although the mechanisms at work require more work to be fully understood. This review addresses a fundamental, yet poorly understood set of evidence of the potential of 5-HT4Rs to re-establish or limit hippocampal alterations related to neurological diseases. Most importantly, the potential of 5-HT4Rs is translated by refining hypotheses regarding the benefits of their activation in memory disorders at the hippocampal level.

Effects of Levothyroxine on Behavior and Cognitive Decline in a Rat Model of Multiple Sclerosis: A Biochemical Study

“…This study also observed learning and memory impairment in rats after LPC injection, consistent with previous findings. Administration of LPC causes neuronal loss in various parts of the hippocampus and results in cognitive impairment (29). Injecting LPC into the CA1 region of the hippocampus triggers microglia to produce pro-inflammatory cytokines (30).…”

Therapeutic Effect of Erythropoietin on Alzheimer’s Disease by Activating the Serotonin Pathway

“…There was a report that 5-HT4R decreases in the hippocampus and cortex of AD patients [ 36 ]. Moreover, 5-HT4R agonists therapy was reported to increase BDNF, a neurogenesis marker, and to enhance synaptic plasticity, making it a potential therapeutic strategy for ameliorating memory, mood, and feeding behavior disturbances [ 16 , 37 ]. The administration of 5-HT7R agonists also reportedly contributed to improved memory formation [ 17 ].…”

“…Several studies have reported a significant loss of 5-HT 4 receptors (5-HT4R) in hippocampal and cortical neurons in AD patients [ 15 ]. The activation of 5-HT4R was shown to benefit cognition in rodents and primates [ 16 ]. A preclinical study suggested that 5-HT7R agonists might be useful in treating memory impairments associated with aging or AD [ 17 ].…”

5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy

“…And that hippocampal-related behavioral task was improved with both 5-HT4R agonists. 5-HT4R/AC/PKA/CREB genes are decreased with exacerbated tau aggregation in human post-mortem brains 5-HT4R plays an essential role in processes related to learning and memory mediated by the dominant synapse to nucleus signaling cascade through AC/cAMP/PKA pathway, modulating the expression of plasticity/learning-related proteins such as BDNF, AKT, and CREB (Roux et al, 2021). To assess the mRNA expression levels of the canonical proteins in this cascade (5-HT4, Gsα, Gβ, Gγ, AC, PKA R, and C subunits and CREB), we performed bioinformatics analyses from bulk and single nucleus RNA sequencing from available datasets.…”