Hippocampal 5HT3A-R mediate social novelty-seeking

Serotonin receptors of class 3 (5HT3-R) are the only subtype of serotonin-gated ion channels which allow for fast synaptic transmissions. Within this family, 5HT3A is the predominant subtype. These receptors are thought to be involved learning, memory and neuroprotection and mutations in HTR3A gene is associated with neuropsychiatric disorders. However, a mechanistic understanding of the role of these receptors in learning and memory is not well understood. Using a gene-trap FLP-dependent conditional knock-in and CRE-dependent conditional knock-out mouse model for 5HT3AR, we show that restoration of 5HT3AR in the hippocampus is sufficient to restore the social novelty preference that was lost in the 5HT3aR knock-out mouse. Moreover, long-term potentiation in the Shaffer collateral-CA1 synapses was absent in 5HT3AR knock-out mice, which was rescued by GABA-A receptor antagonists, suggesting a potential role for GABAergic microcircuits within the hippocampus in social novelty seeking as well as long term potentiation. As such, our present data suggests that 5HT3ARs play a critical role in hippocampal dependent social learning, without affecting other forms of learning that involve the hippocampus.