| First Author | Yu Y | Year | 2022 |
| Journal | Br J Pharmacol | Volume | 179 |
| Issue | 12 | Pages | 2969-2985 |
| PubMed ID | 34997582 | Mgi Jnum | J:349311 |
| Mgi Id | MGI:7640298 | Doi | 10.1111/bph.15793 |
| Citation | Yu Y, et al. (2022) 5-HT(3)(A) receptors maintain hippocampal LTP in a CB(1) and GABA(A) receptor- dependent manner for spatial memory. Br J Pharmacol 179(12):2969-2985 |
| abstractText | BACKGROUND AND PURPOSE: As the only ionotropic receptor in the 5-HT receptor family, the 5-HT(3) receptor (5-HT(3) 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(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-HT(3) 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(3) Rs on axon terminals. It resulted from reduced expression and function of the cannabinoid receptor 1 (CB(1) R) 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-HT(3) R disruption. Consequently, mice with hippocampal 5-HT(3) R 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 CB(1) R-GABA(A) -dependent pathway to regulate spatial memory. |
