Clustered protocadherinβs contribute to configuring functional cell populations in hippocampal-cortical regions

The hippocampus is one of the most important brain regions for memory formation. Memory information is stored in cell populations called memory traces or engrams. However, how these cell populations are formed and selected from among many neurons is unclear. Here, to verify the hypothesis that cell populations are configured by the cellular adhesion molecule clustered protocadherins (Pcdhs), we investigated neuronal activity using immunostaining of the neuronal activity marker c-Fos in hippocampal-cortical regions of mice in which cells expressing Pcdhβ3 are labeled with a fluorescent protein. Reducing Pcdhβ repertoires increased the number of Pcdhβ3⁺ cells expressing c-Fos. The number of c-Fos⁺ Pcdhβ3⁺ cells correlated between hippocampal subregions and between the entorhinal cortex (EC) and hippocampal subregions. Artificial activation of Pcdhβ3⁺ neurons in the EC induced c-Fos expression in the activated neurons of the EC and Pcdhβ3⁺ cells of the hippocampus in a projection-dependent manner. These results indicate that cell populations expressing the same Pcdhβ isoforms form functional cell populations and functionally connect hippocampal-cortical regions. These findings suggest that a specific subset of molecules within individual cells latently defines the neuronal populations that encode memory information. SIGNIFICANCE STATEMENT: The hippocampus is an important brain region for memory formation. Memory information is stored in cell populations called memory traces or engrams. However, the mechanisms underlying the formation of functional cell populations in the hippocampus remain unclear. Here, we show that functional cell populations are latently defined by the molecules clustered protocadherins (Pcdhs) in the hippocampal-cortical regions by observing and manipulating neuronal activity in mice whose cells expressing a specific isoform of Pcdhs are labeled with a fluorescent protein. This study suggests that latent cell populations can function as a fundamental unit for processing information.