The hippocampus is a brain region that plays a central role in learning and memory. Due to its importance, most of the subregions of the hippocampus have been studied exhaustively. However, one of these subregions, the CA2, has avoided the limelight allotted to its neighbors. What are the functional properties of the CA2? What does it wire together with? What role does it play in behavior? Until recently, little has been known.

Hitti and Siegelbaum attack these questions head on in their paper “The hippocampal CA2 region is essential for social memory”. This comprehensive paper walks us through the story of the CA2, from mouse model creation, to circuit tracing, to a series of well-controlled behavioral experiments.

First, the authors start by demonstrating the validity of their Amigo2-Cre mouse line that dominantly targets CA2 pyramidal neurons with both imaging and electrophysiology. Next, they explore the inputs and outputs of the CA2 with molecular tracing. Unsurprisingly, the region is densely interconnected with the other hippocampal structures. Broadly, the CA2 coordinates a strong disynaptic circuit that links the entorhinal cortex to the CA1.


Next, the authors delve into their method for creating a CA2 knock-out. Using an AAV driven virus that expresses tetanus neurotoxin, they demonstrate the silencing of post-synaptic potentials (and preservation of fiber currents) from the CA2.

Now that all this is working, Hitti and Siegelbaum begin the most interesting portion of the paper – the behavior! A slew of social interaction tests are used, the expected result of which is that normal mice will habituate to previously encountered rodents. In comparison to controls, the paper shows that CA2 knockout mice fail to remember previously encountered mice! They fail to habituate, treating every encounter with a familiar mouse as it its first.


What’s truly remarkable is that the authors control for a multitude of confounding factors, social interest, spatial memory, novel object, locomotion, and even olfaction. They find that none of these other factors are significantly different across groups. Quite selectively, the CA2 to mediates social memory.

Taken together, this paper offers a comprehensive demonstration of the necessity for the CA2, a previously poorly defined hippocampal region, in the functioning of social memory in rodents.

Please come join us on Tuesday October 7th, at 4pm in the CNCB  Marilyn Farquhar Seminar Room to hear more about this story from Dr. Steven Siegelbaum!

Debha Amatya is a first-year neurosciences graduate student working in the Gage Lab to understand the relationship between common and rare variants in autism genomics


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