Hippocampal inputs engage CCK+ interneurons to mediate endocannabinoid-modulated feed-forward inhibition in the prefrontal cortex

Abstract

Acknowledgements:We thank the Carter lab for helpful discussions and comments on the 24 manuscript. This work was supported by NIH R01 MH085974 (AGC). The authors have no 25 financial conflicts of interest. 26 2 ABSTRACT 27Connections from the ventral hippocampus (vHPC) to the prefrontal cortex (PFC) regulate 28 cognition, emotion and memory. These functions are also tightly regulated by inhibitory networks 29 in the PFC, whose disruption is thought to contribute to mental health disorders. However, 30relatively little is known about how the vHPC engages different populations of interneurons in the 31 PFC. Here we use slice physiology and optogenetics to study vHPC-evoked feed-forward 32 inhibition in the mouse PFC. We first show that cholecystokinin (CCK+), parvalbumin (PV+), and 33 somatostatin (SOM+) interneurons are prominent in layer 5 (L5) of infralimbic PFC. We then show 34 that vHPC inputs primarily activate CCK+ and PV+ interneurons, with weaker connections onto 35 SOM+ interneurons. CCK+ interneurons make stronger synapses onto pyramidal tract (PT) cells 36 over nearby intratelencephalic (IT) cells. However, CCK+ inputs undergo depolarization-induced 37 suppression of inhibition (DSI) and CB1 receptor modulation only at IT cells. Moreover, vHPC-38 evoked feed-forward inhibition undergoes DSI only at IT cells, confirming a central role for CCK+ 39 interneurons. Together, our findings show how vHPC directly engages multiple populations of 40 inhibitory cells in deep layers of the infralimbic PFC, highlighting unexpected roles for both CCK+ 41 interneurons and endocannabinoid modulation in hippocampal-prefrontal communication. 42