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

Background and Purpose As the only ionotropic receptor in the 5-HT receptor family, the 5-HT3 receptor (5-HT3R) 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(3)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-HT(3)AR knockout or 5-HT(3)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-HT3R 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(3)Rs on axon terminals. It resulted from reduced expression and function of the cannabinoid receptor 1 (CB1R) co-localized with 5-HT(3)Rs on axon terminals, and then led to diminishment of tonic inhibition of GABA release by CB(1)Rs. Inhibition of CB(1)Rs mimicked the facilitation of GABAergic transmission by 5-HT3R disruption. Consequently, mice with hippocampal 5-HT3R disruption exhibited impaired spatial memory in MWM tasks. Conclusion and Implications These results suggest that 5-HT(3)Rs are crucial in enabling hippocampal synaptic plasticity via a novel CB1R-GABA(A)-dependent pathway to regulate spatial memory.

Automated summary

This study found that dysfunction of the 5-HT3R affects synaptic plasticity between hippocampal neurons, leading to impairment in spatial memory. This effect is mediated through the CB1R-GABA(A) pathway on the 5-HT3R.