General anesthesia is widely utilized in the clinic for surgical and diagnostic procedures. However, growing evidence suggests that
anesthetic exposure may affect cognitive function negatively. Unfortunately, little is known about the underlying mechanisms and efficient prevention and therapeutic strategies for the
anesthesia-induced
cognitive dysfunction. 5-HT7R, a
serotonin receptor family member, is functionally associated with learning and memory. It has recently become a potential therapeutic target in various neurological diseases as its
ligands have a wide range of neuropharmacological effects. However, it remains unknown the role of 5-HT7R in the long-term
isoflurane anesthesia-induced memory impairment and whether prior activation or blockade of 5-HT7R before
anesthesia has modulating effects on this memory impairment. In this study, 5-HT7R selective agonist
LP-211 and 5-HT7R selective antagonist
SB-269970 were pretreated intraperitoneally to mice before
anesthesia; their effects on the cognitive performance of mice were assessed using fear conditioning test and novel object recognition test. Furthermore, the transcriptional level of 5-HT7R in the hippocampus was detected using qRT-PCR, and proteomics was conducted to probe the underlying mechanisms. As a result, long-term exposure to
isoflurane anesthesia caused memory impairment and an increase in hippocampal 5-HT7R
mRNA expression, which could be attenuated by
SB-269970 pretreatment but not LP-211pretreatment. According to the proteomics results, the antiamnestic effect of
SB-269970 pretreatment was probably attributed to its action on the gene expression of Slc6a11, Itpka, Arf3, Srcin1, and
Epb41l2, and synapse organization in the hippocampus. In conclusion, 5-HT7R is involved in the memory impairment induced by long-term
isoflurane anesthesia, and the prior blockade of 5-HT7R with
SB-269970 protects the memory impairment. This finding may help to improve the understanding of the long-term
isoflurane anesthesia-induced memory impairment and to construct potential preventive and therapeutic strategies for the adverse effects after long-term
isoflurane exposure.