Cell type-specific genetic and optogenetic tools reveal novel hippocampal CA2 circuits

The formation and recall of episodic memory requires precise information processing by the entorhinal-hippocampal network. For several decades, the trisynaptic circuit, entorhinal cortex layer II (ECII)→dentate gyrus (DG)→CA3→CA1 and the monosynaptic circuit ECIII→CA1 have been considered the main substrates of the network responsible for learning and memory. Circuits linked to another hippocampal region, CA2, have only recently come to light. Here, by using highly cell type-specific transgenic mouse lines, optogenetics, and patch-clamp recordings, we show that DG cells, long believed not to project to CA2, send functional monosynaptic inputs to CA2 pyramidal cells, through abundant longitudinal projections. CA2 innervates CA1 to complete an alternate trisynaptic circuit but, unlike CA3, projects preferentially to the deep rather than superficial sublayer of CA1. Furthermore, contrary to the current knowledge, ECIII does not project to CA2. These new anatomical results will allow for a deeper understanding of the biology of learning and memory.