5-HT_3A receptors maintain hippocampal LTP in a CB₁ and GABA_A receptor- dependent manner for spatial memory

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.

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.

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.

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