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The 5-hydroxytryptamine type-3A receptor (5-HT3AR) as the only ligand-gated ion channel in serotonin receptor family is known to involve in emotion regulation in central nervous system.However, the physiological role of 5-HT3AR in synaptic plasticity and memory remains unclear.Here we show that in the CA1 region of mouse hippocampus, pharmacological blockade (ondansetron, 25 nM) or genetic deletion of 5-HT3AR specifically impaired long-term potentiation (LTP) induced by theta burst or 200 Hz high frequency stimulation, while basal glutamatergic neurotransmission was not affected by 5-HT3AR perturbations.Moreover, behavioral studies showed that 5-HT3AR knock-out mice exhibited impaired hippocampus-dependent learning and memory in morris water maze, but had no change in motor coordination and balance.These results reveal a direct role of 5-HT3AR in hippocampal synaptic plasticity and spatial memory, which possibly serve as an interface between emotional and cognitive processes.