NPAS4 recruits CCK basket cell synapses and enhances cannabinoid-sensitive inhibition in the mouse hippocampus.

Andrea L Hartzell,G Stefano Brigidi,Daniel A Heinz,Brenda L Bloodgood,Kelly M Martyniuk,Anja Payne,Nathalie A Djaja

doi:10.7554/elife.35927

Andrea L Hartzell, G Stefano Brigidi + Show 5 more

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https://doi.org/10.7554/elife.35927

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Journal: eLife	Publication Date: Jul 27, 2018
Citations: 41	License type: CC BY 4.0

Affiliation: University of California, San Diego

Abstract

Experience-dependent expression of immediate-early gene transcription factors (IEG-TFs) can transiently change the transcriptome of active neurons and initiate persistent changes in cellular function. However, the impact of IEG-TFs on circuit connectivity and function is poorly understood. We investigate the specificity with which the IEG-TF NPAS4 governs experience-dependent changes in inhibitory synaptic input onto CA1 pyramidal neurons (PNs). We show that novel sensory experience selectively enhances somatic inhibition mediated by cholecystokinin-expressing basket cells (CCKBCs) in an NPAS4-dependent manner. NPAS4 specifically increases the number of synapses made onto PNs by individual CCKBCs without altering synaptic properties. Additionally, we find that sensory experience-driven NPAS4 expression enhances depolarization-induced suppression of inhibition (DSI), a short-term form of cannabinoid-mediated plasticity expressed at CCKBC synapses. Our results indicate that CCKBC inputs are a major target of the NPAS4-dependent transcriptional program in PNs and that NPAS4 is an important regulator of plasticity mediated by endogenous cannabinoids.

Highlights

IntroductionImmediate-early gene transcription factors (IEG-TFs) are expressed in response to sensory experiences and are routinely used to identify task-relevant neurons (Bullitt, 1990; Guenthner et al, 2013; Renier et al, 2016; Ye et al, 2016), including those associated with memory formation and behavioral plasticity (Alen et al, 2013; Cai et al, 2016; Cowansage et al, 2014; Garner et al, 2012; Mayford and Reijmers, 2015)
Determining the identity of the inhibitory synapses that are regulated by neuronal PAS domain protein 4 (NPAS4) is critical for understanding how this Immediate-early gene transcription factors (IEG-TFs) could alter circuit function
We have taken advantage of the mutually exclusive receptor and channel expression and electrophysiological signatures of PV- and CCKBCs to reveal the identity of somatic inhibitory synapses that are regulated by NPAS4

Summary

Introduction

Immediate-early gene transcription factors (IEG-TFs) are expressed in response to sensory experiences and are routinely used to identify task-relevant neurons (Bullitt, 1990; Guenthner et al, 2013; Renier et al, 2016; Ye et al, 2016), including those associated with memory formation and behavioral plasticity (Alen et al, 2013; Cai et al, 2016; Cowansage et al, 2014; Garner et al, 2012; Mayford and Reijmers, 2015) In spite of their wide-spread use as tools, surprisingly little is known about how IEG-TFs alter connectivity between specific neuron subtypes, influence plasticity, or impact circuit function (Minatohara et al, 2015). We do not know whether the expression of NPAS4 in PNs leads to the regulation of synapses made by specific inhibitory neuron subtypes

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