The trisynaptic circuit, which is composed of connections from entorhinal cortex to dentate gyrus to CA3 and ultimately to CA1, has long been considered to be the canonical pathway for information flow through the hippocampus and is thought to form the anatomical substrate for learning and memory in this region. Much less is known about the CA2 region, although recent work has suggested that neurons in this area can be uniquely identified by their gene expression patterns, opening up a new avenue for understanding their role in information flow through the hippocampus. On page 269 of this issue, Kohara and colleagues capitalize on these previously unknown molecular markers, using cell type–specific transgenic mouse lines, optogenetics and patch-clamp recordings to identify the unique connectivity patterns of hippocampal CA2 pyramidal neurons.

Although the CA2 region (yellow) has historically been differentiated from CA1 and CA3, in part, on the basis of the absence of input from the dentate gyrus, the authors find that dentate granule cells (cyan) do indeed send abundant functional monosynaptic inputs to CA2 pyramidal cells (red). They also identify a projection from CA2 to CA1, but, unlike the projection from CA3 to CA1, CA2 projects preferentially to the deep rather than to the superficial sublayer of CA1. In addition, in contrast with previous studies using more traditional anatomical techniques, the authors report that neurons in layer III of the entorhinal cortex do not project to CA2.

Although the exact role that these hippocampal connectivity patterns may have in learning and memory processes remains unclear, these findings present exciting opportunities for future research.