5-HT3A receptors maintain hippocampal LTP in a CB1 and GABAA receptor- dependent manner for spatial memory.

Abstract

BACKGROUND AND PURPOSE:

As the only ionotropic receptor in the 5-HT receptor family, the 5-HT3 receptor (5-HT3 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-HT3 Rs shape synaptic plasticity for memory function.

EXPERIMENTAL APPROACH:

Extracellular as well as whole-cell electrophysiological recordings were used to monitor hippocampal LTP and synaptic transmission in hippocampal slices in 5-HT3 AR knockout or 5-HT3 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.

KEY RESULTS:

We found that 5-HT3 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-HT3 Rs on axon terminals. It resulted from reduced expression and function of the cannabinoid receptor 1 (CB1 R) co-localized with 5-HT3 Rs on axon terminals, and then led to diminishment of tonic inhibition of GABA release by CB1 Rs. Inhibition of CB1 Rs mimicked the facilitation of GABAergic transmission by 5-HT3 R disruption. Consequently, mice with hippocampal 5-HT3 R disruption exhibited impaired spatial memory in MWM tasks.

CONCLUSION AND IMPLICATIONS:

These results suggest that 5-HT3 Rs are crucial in enabling hippocampal synaptic plasticity via a novel CB1 R-GABAA -dependent pathway to regulate spatial memory.

• Authors: Yan Yu, Jing-Jing Li, Xiao-Qian He, Zi-Ying Lai, Rui Hao, Yu Qi, Dong-Qing Cao, Ming Fu, Hong Ma, Qiu-Chen Xie, Mu Sun, Zhi-Li Huang, Ling-Jing Jin, Hui-Hui Sun, Ning Lu, Rui Wang, Wing-Ho Yung, Ying Huang
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 179 Issue 12 Pg. 2969-2985 (06 2022) ISSN: 1476-5381 [Electronic] England
• PMID: 34997582 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The British Pharmacological Society.

Chemical References

• Receptor, Cannabinoid, CB1
• Receptors, GABA-A
• Serotonin
• gamma-Aminobutyric Acid

Topics

• Animals
• CA1 Region, Hippocampal (metabolism)
• Hippocampus (metabolism)
• Humans
• Long-Term Potentiation (physiology)
• Memory Disorders (metabolism)
• Mice
• Receptor, Cannabinoid, CB1 (genetics, metabolism)
• Receptors, GABA-A (metabolism)
• Serotonin (metabolism)
• Spatial Memory
• gamma-Aminobutyric Acid (metabolism)