Transgenically-targeted increase in the activity of medial entorhinal layer II neurons induces reversible field expansion and remapping of CA1 place cells

The hippocampal formation plays a critical role in memory acquisition and consolidation. Hippocampal pyramidal neurons fire in a location-specific manner. These “place” cells are thought to generate an internal representation of context dependent space. In a mouse model, we induced transgenic expression in layer II medial entorhinal cortex of a modified muscarinic G-protein coupled receptor that selectively binds clozapine-N-oxide. CNO, an otherwise inert metabolite of the antipsychotic clozapine, is a small molecule drug capable of crossing the blood-brain barrier. Binding of CNO to the receptor triggers an intracellular cascade ultimately resulting in the depolarization of the cell, and thus increased firing that lasts for several hours. We analyzed CA1 place fields before and after CNO injection. Many neurons expanded their place fields following grid cell activation, as predicted by models of grid cell to place cell transformations. However, other neurons drastically changed their firing fields (i.e. they “remapped”), while others were unchanged by CNO. All effects reversed twelve hours post injection. These effects underscore the generative nature of the hip- pocampal network, and provide empirical data to distinguish between theoretical models of place field formation.