Entorhinal Cholecystokinin Enables Theta-Burst Stimulation-Induced Hippocampal LTP and Transfer of Spatial Memory

Cholecystokinin (CCK) is purported to be involved in neuroplasticity and memory encoding.  Here we found that CCK from the medial entorhinal (MEC) to hippocampus projections facilitated CA3-CA1 long-term potentiation (LTP), which further enabled spatial memory transfer. CCK knockout mice lacked theta-burst stimulation-induced CA3-CA1 LTP and their spatial memory were compromised. Upon high-frequency optical activation, the MEC CCKergic terminals in the hippocampus released CCK and induced CA3-CA1 LTP, mainly through CCK A receptors. However, down-regulation of the MEC Cck expression impaired LTP. Stimulation of hippocampal CCK neurons, the Schaffer Collaterals, or the inhibitory MEC to hippocampus terminals, induced no CA3-CA1 LTP. Activation of a group of CA1 pyramidal neurons when the mouse visited a certain place of an arena, induced primed place cells (PPCs). The CCK-strengthened connectivity of two groups of PPCs enabled the transfer of fear memory from one place to another, implicating CCK’s determining role in spatial memory encoding.