Dichotomous Effects of Mu Opioid Receptor Activation on Striatal Low-Threshold Spike Interneurons.

Rasha Elghaba,Enrico Bracci

doi:10.3389/fncel.2017.00385

Rasha Elghaba, Enrico Bracci

Open Access

https://doi.org/10.3389/fncel.2017.00385

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Abstract

Striatal low-threshold spike interneurons (LTSIs) are tonically active neurons that express GABA and nitric oxide synthase and are involved in information processing as well as neurovascular coupling. While mu opioid receptors (MORs) and their ligand encephalin are prominent in the striatum, their action on LTSIs has not been investigated. We addressed this issue carrying out whole-cell recordings in transgenic mice in which the NPY-expressing neurons are marked with green fluorescent protein (GFP). The MOR agonist (D-Ala(2), N-MePhe(4), Gly-ol)-enkephalin (DAMGO) produced dual effects on subpopulations of LTSIs. DAMGO caused inhibitory effects, accompanied by decreases of spontaneous firing, in 62% of LTSIs, while depolarizing effects (accompanied by an increase in spontaneous firing) were observed in 23% of LTSIs tested. The dual effects of DAMGO persisted in the presence of tetrodotoxin (TTX), a sodium channel blocker or in the presence of the nicotinic acetylcholine receptor antagonist mecamylamine. However, in the presence of either the GABAA receptor antagonist picrotoxin or the muscarinic cholinergic receptor antagonist atropine, DAMGO only elicited inhibitory effects on LTSIs. Furthermore, we found that DAMGO decreased the amplitude and frequency of spontaneous GABAergic events. Unexpectedly, these effects of DAMGO on spontaneous GABAergic events disappeared after blocking of the muscarinic and nicotinic cholinergic blockers, showing that GABA inputs to LTSIs are not directly modulated by presynaptic MORs. These finding suggest that activation of MORs affect LTSIs both directly and indirectly, through modulation of GABAergic and cholinergic tones. The complex balance between direct and indirect effects determines the net effect of DAMGO on LTSIs.

Highlights

Striatal low-threshold spike interneurons (LTSIs) are GABAergic cells that were originally identified by Kawaguchi and colleagues as cells expressing neuropeptide Y (NPY), somatostatin and nitric oxide synthase (Kawaguchi, 1993; Kubota and Kawaguchi, 2000)
The main conclusion of this study is that activation of mu opioid receptors (MORs) has a complex influence on striatal LTSIs, which is mediated through a combination of direct inhibitory effects, a decrease of cholinergic tone and a decrease of GABAergic tone
MOR activation can cause either strong hyperpolarizations or strong depolarizations in LTSIs, in a manner that reflects the relative contribution of these three events to the excitability of individual interneurons

Summary

Introduction

Striatal low-threshold spike interneurons (LTSIs) are GABAergic cells that were originally identified by Kawaguchi and colleagues as cells expressing neuropeptide Y (NPY), somatostatin and nitric oxide synthase (Kawaguchi, 1993; Kubota and Kawaguchi, 2000). Mu opioid receptors (MORs) are prominent in the striatum, being abundantly expressed and mediating the effects of the neuropeptide enkephalin, that is released by projection neurons expressing D1 dopamine receptors (Miura et al, 2007, 2008; Blomeley and Bracci, 2011; Atwood et al, 2014) This issue is of interest, because, if MOR controlled the activity of LTSIs, a reciprocal control between these cells and D1-expressing projection neurons could be present. Both nitric oxide (Rafalovich et al, 2015) and enkephalin (Atwood et al, 2014) have been shown to induce long term depression in the striatum and it is important to unravel the interactions between nitrergic and opioidergic neurons.

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