5-HT1A Receptor Agonist Promotes Retinal Ganglion Cell Function by Inhibiting OFF-Type Presynaptic Glutamatergic Activity in a Chronic Glaucoma Model.

Xujiao Zhou,Gang Li,Shenghai Zhang,Jihong Wu

doi:10.3389/fncel.2019.00167

Abstract

Serotonin receptors are potential neuroprotective agents in degenerative diseases of the central nervous system. The protective effects of serotonin receptor (5-HT1A) agonists on the survival and function of retinal ganglion cells (RGCs) by regulating the release of the presynaptic neurotransmitter γ-aminobutyric acid (GABA) were confirmed in our previous study of a chronic glaucoma rat model. However, the roles of excitatory amino acids and their interactions with the 5-HT1A receptor in glaucoma remain unknown. Here, we found that ocular hypertension increased glutamine synthetase (GS) and excitatory amino acid transporter 2 (EAAT2) expression in rat retinas. In addition, the high expression of GS and EAAT2 induced by glaucoma was downregulated by the 5-HT1A receptor agonist 8-OH-DPAT and the 5-HT1A receptor antagonist WAY-100635, respectively. Patch-clamp techniques were used to record glutamate receptor-mediated spontaneous and miniature glutamatergic excitatory post-synaptic currents (sEPSCs and mEPSCs) as well as L-glutamate-induced current in OFF-type and ON-type RGCs in rat retinal slices. Although there were no significant differences in the frequency and amplitude of sEPSC and mEPSC release between normal and glaucoma OFF- and ON-type RGCs, exogenous 8-OH-DPAT administration specifically reduced the frequency, but not the amplitude, of sEPSC and mEPSC release in glaucoma OFF-type rather than ON-type RGCs; these effects were completely blocked by WAY-100635. In summary, 8-OH-DPAT decreases and increases GS and EAAT2 expression of glaucomatous retina, respectively, while decreasing sEPSC and mEPSC frequency. In contrast, WAY-100635 increases and decreases GS and EAAT2 expression of glaucomatous retina, respectively, while increasing sEPSC and mEPSC frequency. The reduction of glutamatergic presynaptic transmission by 8-OH-DPAT deactivates RGCs at the neural network level and reduces the excitotoxic damage in the pathological process of chronic glaucoma.

Highlights

Serotonin [5-hydroxytryptamine (5-HT)] can be synthesized by many types of neurons in the central nervous system (CNS)
These findings indicate that stimulation of 5-HT1A receptors in the retina attenuates glaucoma-induced increases in glutamine synthetase (GS) protein expression
Whole-cell patch-clamp recordings demonstrated that administration of 8-OH-DPAT significantly decreases the frequency, but not the amplitude, of glutamatergic sEPSC in OFF-type retinal ganglion cells (RGCs), with similar results for mEPSCs

Summary

Introduction

Serotonin [5-hydroxytryptamine (5-HT)] can be synthesized by many types of neurons in the central nervous system (CNS). The retina is the epitaxial part of the CNS Both clinical and basic studies have found that serotonin is very important in the regulation of retinal ganglion cells (RGCs) (Hidaka, 2009). Convincing evidence demonstrates that serotonin exists in the mammalian retina (Osborne et al, 1981; Chanut et al, 2002) and has many functions, including altering retinal amacrine cell processing; serotonin is expressed in the aqueous humor of the eyes, while 5-HT1A receptor agonist can reduce intraocular pressure (IOP) in rabbits, but not in monkeys (George et al, 2005; Sharif, 2010). RT-PCR studies have revealed that the 5-HT1A, 5-HT2A, 5-HT2C, 5-HT2C, 5-HT3, and 5-HT7 receptor subtypes are expressed in the retinas of rats (Sharif and Senchyna, 2006), suggesting that the monoamine system plays an important role in the regulation of visual function

Methods

Results

Conclusion