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

Xingchen Liu,Jordane Dimidschstein,Adam G Carter,Gordon Fishell

doi:10.7554/elife.55267

Xingchen Liu, Jordane Dimidschstein + Show 2 more

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https://doi.org/10.7554/elife.55267

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Journal: eLife	Publication Date: Oct 9, 2020
Citations: 20	License type: CC BY 4.0

Affiliation: Broad Institute, New York University

Abstract

Connections from the ventral hippocampus (vHPC) to the prefrontal cortex (PFC) regulate cognition, emotion, and memory. These functions are also tightly controlled by inhibitory networks in the PFC, whose disruption is thought to contribute to mental health disorders. However, relatively little is known about how the vHPC engages different populations of interneurons in the PFC. Here we use slice physiology and optogenetics to study vHPC-evoked feed-forward inhibition in the mouse PFC. We first show that cholecystokinin (CCK+), parvalbumin (PV+), and somatostatin (SOM+) expressing interneurons are prominent in layer 5 (L5) of infralimbic PFC. We then show that vHPC inputs primarily activate CCK+ and PV+ interneurons, with weaker connections onto SOM+ interneurons. CCK+ interneurons make stronger synapses onto pyramidal tract (PT) cells over nearby intratelencephalic (IT) cells. However, CCK+ inputs undergo depolarization-induced suppression of inhibition (DSI) and CB1 receptor modulation only at IT cells. Moreover, vHPC-evoked feed-forward inhibition undergoes DSI only at IT cells, confirming a central role for CCK+ interneurons. Together, our findings show how vHPC directly engages multiple populations of inhibitory cells in deep layers of the infralimbic PFC, highlighting unexpected roles for both CCK+ interneurons and endocannabinoid modulation in hippocampal-prefrontal communication.

Highlights

The prefrontal cortex (PFC) controls cognitive and emotional behaviors (Euston et al, 2012; Miller and Cohen, 2001) and is disrupted in many neuropsychiatric disorders (Godsil et al, 2013; Sigurdsson and Duvarci, 2015)
We first show that cholecystokinin (CCK+), parvalbumin (PV+), and somatostatin (SOM+) interneurons are prominent in layer 5 (L5) of infralimbic PFC
While we observed cannabinoid type 1 receptor (CB1R)+ puncta in L5 around the cell bodies of both cell types (Fig. 6A), their density was greater at IT cells (Fig. 6B; IT = 9.3 ± 0.5 puncta / cell, pyramidal tract (PT) = 5.7 ± 0.5 puncta / cell, p < 0.0001; n = 4 animals, 247 IT cells, PT cells). These results indicate that presynaptic CB1Rs are more prominent at perisomatic connections onto IT cells, suggesting why these inputs are more strongly affected by depolarization-induced suppression of inhibition (DSI)

Summary

Introduction

The prefrontal cortex (PFC) controls cognitive and emotional behaviors (Euston et al, 2012; Miller and Cohen, 2001) and is disrupted in many neuropsychiatric disorders (Godsil et al, 2013; Sigurdsson and Duvarci, 2015). Dysfunction of vHPC to PFC connectivity is implicated in schizophrenia, anxiety disorders, chronic stress disorders, and depression (Godsil et al, 2013; Sigurdsson and Duvarci, 2015) To understand these roles, it is necessary to establish how vHPC inputs engage local excitatory and inhibitory networks within the PFC. The vHPC primarily projects to the ventral medial PFC in rodents, with axons most prominent in layer 5 (L5) of infralimbic (IL) PFC (Phillips et al, 2019) These excitatory inputs contact multiple populations of pyramidal cells, and are much stronger at intratelencephalic (IT) cells than nearby pyramidal tract (PT) cells (Liu and Carter, 2018).

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