Differential Modulation of GABAA and NMDA Receptors by an α7-nicotinic Acetylcholine Receptor Agonist in Chronic Glaucoma.

Xujiao Zhou,Rong Zhang,Xuejin Zhang,Jihong Wu,Yuan Zong,Xinghuai Sun,Shenghai Zhang

doi:10.3389/fnmol.2017.00422

Abstract

Presynaptic modulation of γ-aminobutyric acid (GABA) release by an alpha7 nicotinic acetylcholine receptor (α7-nAChR) agonist promotes retinal ganglion cell (RGC) survival and function, as suggested by a previous study on a chronic glaucomatous model from our laboratory. However, the role of excitatory and inhibitory amino acid receptors and their interaction with α7-nAChR in physiological and glaucomatous events remains unknown. In this study, we investigated GABAA and N-methyl-D-aspartate (NMDA) receptor activity in control and glaucomatous retinal slices and the regulation of amino acid receptor expression and function by α7-nAChR. Whole-cell patch-clamp recordings from RGCs revealed that the α7-nAChR specific agonist PNU-282987 enhanced the amplitude of currents elicited by GABA and reduced the amplitude of currents elicited by NMDA. The positive modulation of GABAA receptor and the negative modulation of NMDA receptor (NMDAR) by PNU-282987-evoked were prevented by pre-administration of the α7-nAChR antagonist methyllycaconitine (MLA). The frequency and the amplitude of glutamate receptor-mediated miniature glutamatergic excitatory postsynaptic currents (mEPSCs) were not significantly different between the control and glaucomatous RGCs. Additionally, PNU-282987-treated slices showed no alteration in the frequency or amplitude of mEPSCs relative to control RGCs. Moreover, we showed that expression of the α1 subunit of the GABAA receptor was downregulated and the expression of the NMDAR NR2B subunit was upregulated by intraocular pressure (IOP) elevation, and the changes of high IOP were blocked by PNU-282987. In conclusion, retina GABAA and NMDARs are modulated positively and negatively, respectively, by activation of α7-nAChR in in vivo chronic glaucomatous models.

Highlights

Interactions between the cholinergic, γ-aminobutyric acidergic (GABAergic) and glutamatergic systems, as the major neurotransmitters in the central nervous system (CNS), are involved in many neurodevelopmental, neurological and neurodegenerative disorders (Mittag et al, 2000; Sattler and Tymianski, 2001; Lin et al, 2014a; Lewerenz and Maher, 2015)
We further examined if glutamatergic synaptic inputs in glaucomatous retinal slices were affected by examining the miniature glutamatergic excitatory postsynaptic currents of retinal ganglion cell (RGC)
We further examined if NMDA receptor (NMDAR) function was changed in glaucomatous retinal slices by examining the NMDA-elicited whole-cell currents of RGCs in the retina

Summary

Introduction

Interactions between the cholinergic, γ-aminobutyric acidergic (GABAergic) and glutamatergic systems, as the major neurotransmitters in the central nervous system (CNS), are involved in many neurodevelopmental, neurological and neurodegenerative disorders (Mittag et al, 2000; Sattler and Tymianski, 2001; Lin et al, 2014a; Lewerenz and Maher, 2015). Alpha nicotinic acetylcholine receptor (α7-nAChR)–knockout mice exhibit reduced cortical NMDARs and glutamatergic synapses (Lin et al, 2014b) and decreased cortical levels of GABAergic markers (Liu et al, 2006; Lin et al, 2014a). The major neurotransmitters, GABA and glutamate, are relevant to ocular diseases through excessive neuronal excitability resulting from the hypofunction of inhibitory signaling or the overexpression of NMDARs (Shareef et al, 1995; Mittag et al, 2000; Sattler and Tymianski, 2001; Dmitrieva et al, 2007; Chen et al, 2011; Seung and Sümbül, 2014; Li et al, 2017). To examine the neuronal circuit changes associated with glaucoma in greater detail, the relationship between α7-nAChR and amino acid receptors in the retina must be explored

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Conclusion