CA3 NMDA receptors are required for experience-dependent shifts in hippocampal activity

The anatomical distribution of sensory-evoked activity recorded from the hippocampal long-axis can shift depending on prior experience. In accordance with Marr's computational model of hippocampal function, CA3 NMDA receptors have been hypothesized to mediate this experience-dependent shift in hippocampal activity. Here we tested this hypothesis by investigating genetically-modified mice in which CA3 NMDA receptors are selectively knocked-out (CA3-NR1 KO). First, we were required to develop an fMRI protocol that can record sensory-evoked activity from the mouse hippocampal long-axis. This goal was achieved in part by using a dedicated mouse scanner to image odor-evoked activity, and by using non-EPI (echo planer imaging) pulse sequences. As in humans, odors were found to evoke a ventral-predominant activation pattern in the mouse hippocampus. More importantly, odor-evoked activity shifted in an experience-dependent manner. Finally, we found that the experience-dependent shift in hippocampal long-axis activity is blocked in CA3-NR1 knock-out mice. These findings establish a cellular mechanism for the plasticity imaged in the hippocampal long-axis, suggesting how experience-dependent modifications of hippocampal activity can contribute to its mnemonic function.