New hippocampal anatomy by optogenetics "Input and output circuits of CA2"
Keigo Kohara, Michele Pignatelli, Alexander J Rivest, Hae-Yoon Jung, Takashi Kitamura, Junghyup Suh, Dominic Frank, Koichiro Kajikawa, Nathan Mise, Yuichi Obata, Ian R Wickersham and Susumu Tonegawa
Formation of episodic memory requires precise information routing in the hippocampus. For more than a hundred years, the trisynaptic circuit has been considered the main anatomical substrate of the hippocampal circuitry responsible for learning and memory. However, the hippocampus includes a region located between CA3 and CA1, named "CA2", whose intrahippocampal connectivity has remained elusive. Here, by using cell type-specific transgenic mice, optogenetics and patch-clamp recordings we show that DG cells, long believed not to project to the CA2, send functional monosynaptic inputs to CA2. While the DG-CA3 pathway mostly follows a lamellar organization, the DG-CA2 pathway extends longitudinally. Furthermore, CA2 preferentially projects to the deep rather than superficial sublayers of CA1 while CA3 projects equally to the two CA1 sublayers. Then, we examined other outputs of CA2 neurons. These findings redefine hippocampal anatomy by revealing a parallel trisynaptic circuit, DG-CA2-CA1deep, which complements the established DG-CA3-CA1 route, allowing a deeper understanding of the biology of learning and memory.
1RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive
Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 2RIKEN BioResource Center, Tsukuba, Ibaraki, Japan. 3Genetic Neuroengineering
Group, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.