Yu Yan, Li Jing-Jing, He Xiao-Qian, Lai Zi-Ying, Hao Rui, Qi Yu, Cao Dong-Qing, Fu Ming, Ma Hong, Xie Qiu-Chen, Sun Mu, Huang Zhi-Li, Jin Ling-Jing, Sun Hui-Hui, Lu Ning, Wang Rui, Yung Wing-Ho, Huang Ying
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Ministry of Education), Department of Physiology and Pharmacology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Pharmacy, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
Br J Pharmacol. 2022 Jun;179(12):2969-2985. doi: 10.1111/bph.15793. Epub 2022 Feb 14.
As the only ionotropic receptor in the 5-HT receptor family, the 5-HT receptor (5-HT R) is involved in psychiatric disorders and its modulators have potential therapeutic effects for cognitive impairment in these disorders. However, it remains unclear how 5-HT Rs shape synaptic plasticity for memory function.
Extracellular as well as whole-cell electrophysiological recordings were used to monitor hippocampal LTP and synaptic transmission in hippocampal slices in 5-HT AR knockout or 5-HT AR-GFP mice. Immunocytochemistry, qRT-PCR and western blotting were used to measure receptor expression. We also assessed hippocampal dependent cognition and memory, using the Morris water maze (MWM) and novel object recognition.
We found that 5-HT R dysfunction impaired hippocampal LTP in Schaffer collateral (SC)-CA1 pathway in hippocampal slices, by facilitating GABAergic inputs in pyramidal cells. This effect was dependent on 5-HT Rs on axon terminals. It resulted from reduced expression and function of the cannabinoid receptor 1 (CB R) co-localized with 5-HT Rs on axon terminals, and then led to diminishment of tonic inhibition of GABA release by CB Rs. Inhibition of CB Rs mimicked the facilitation of GABAergic transmission by 5-HT R disruption. Consequently, mice with hippocampal 5-HT R disruption exhibited impaired spatial memory in MWM tasks.
These results suggest that 5-HT Rs are crucial in enabling hippocampal synaptic plasticity via a novel CB R-GABA -dependent pathway to regulate spatial memory.
