The ability to remember familiar conspecifics, termed social memory, is critical for an animal’s behaviour in its social environment. In recent years, extensive evidence supports the importance of distinct hippocampal subregions, dorsal CA2 (dCA2) and ventral CA1 (vCA1) in the regulation of social memory. However, little is known about the relevant input regions. Here, we present evidence that the medial septum (MS), sends inputs to the hippocampus that are required for social memory. Furthermore, we find that 5-HT modulation of the MS bi-directionally influences social memory formation.

Using TRAP2;Ai14 mice as an unbiased approach for identifying dCA2 and vCA1 input regions that are activated during social encounters, we identified elevated activity in the MS. Inhibition of the MS→dCA2 projection, but not the MS→vCA1 projection impaired social memory. Strikingly, excitation of the MS can prolong social memory. Moreover, we show elevated MS cell activity during social interactions, which is modulated by 5-HT1b receptors® and 5-HT release from the median raphe. This elevated activity in turn plays a role in establishing plasticity in the downstream dCA2 pyramidal neurons, a process crucial for social memory formation. Surprisingly, a 5-HT1bR agonist infused into the MS can prolong social memory in wild-type mice and rescue social memory deficits in an autism-associated mouse model with social memory deficits. This finding may prove therapeutically beneficial since social memory is commonly impaired in autism. Together these findings reveal a 5-HT modulated MS→dCA2 circuit that is required for the regulation of social memory.