Selective activation of mGluR8 receptors modulates retinal ganglion cell light responses

Abstract

Extracellular and whole-cell light-evoked responses of mouse retinal ganglion cells were recorded in the presence of the mGluR8 selective agonist, (S) . Off-light responses were reversibly reduced in the presence of DCPG in wild-type but not in mGluR8-deficient retinas. On-responses were only marginally modulated by DCPG. During Off-responses, DCPG suppressed both excitatory and inhibitory synaptic conductances suggesting that mGluR8 receptor activity reduces glutamate release from bipolar cell terminals and possibly also the release of an inhibitory neurotransmitter from amacrine cell processes. Keywords Retina; metabotropic glutamate receptorGlutamate is the main excitatory neurotransmitter in the retina mediating transmission from photoreceptors to bipolar cells, and from bipolar cells to amacrine and ganglion cells. It exerts its effects via ionotropic and metabotropic receptors, thus serving multiple roles in visual signal processing (for reviews see Brandstätter et al., 1998;Thoreson and Witkovsky, 1999). Ionotropic glutamate receptors (NMDA, AMPA, and kainate subtypes) are ligand-gated ion channels that activate non-selective cation channels (Hollmann and Heinemann, 1994). Metabotropic glutamate receptors (mGluRs) can be either pre-or postsynaptic, and modulate G protein-mediated intracellular second messenger cascades that elicit diverse effects on neuronal function (Pin and Duvoisin, 1995).The mGluRs are classified into three groups based on sequence homology, second messenger coupling and pharmacological selectivity (Conn and Pin, 1997). Group-I receptors (mGluR1 and 5) are coupled to the stimulation of phospholipase C, whereas group-II (mGluR2 and 3) and 6, 7, and 8) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 March 31. Hartveit et al., 1995).The best functionally characterized of the retinal mGluRs is the group-III receptor mGluR6, which occurs postsynaptically at the dendritic tips of On-bipolar cells (Nomura et al., 1994). The mGluR6 receptors transduce the light-evoked hyperpolarization of photoreceptors into a depolarizing response at bipolar cells by gating an excitatory cation channel (Slaughter and Miller, 1981;Shiells and Falk, 1990;Nawy and Jahr, 1991). The compound, L-2-amino-4-phosphonobutyrate (L-AP4, also L-APB), is a selective agonist of group-III mGluRs and its activation of mGluR6 has been widely used to selectively block the On-pathway (Massey et al., 1983;Schiller et al., 1986;Bodnarenko and Chalupa, 1993;Kittila and Massey, 1995). Howeve...

Differential modulation of retinal ganglion cell light responses by orthosteric and allosteric metabotropic glutamate receptor 8 compounds

“…The effects of 1 μM DCPG on the OFF excitatory current were significantly different from that of 10 μM AZ (p < 0.05) for both bright and dim stimuli, whereas the differing effect of these drugs on the outward currents approached statistical significance (p = 0.06). This reduction of the amplitude of the excitatory OFF response under DCPG is consistent with previous results (Awatramani and Slaughter, 2001; Higgs et al, 2002; Quraishi et al, 2010) further suggesting that mGluR8 is expressed within the direct OFF excitatory pathway for OFF ganglion cells.…”

“…The effects of DCPG on the light responses of ganglion cells were consistent with our previous report of a decrease in spiking activity associated with OFF responses (Quraishi et al, 2010). Both ON and OFF excitatory currents in OFF-transient and ON-OFF-ganglion cells were reduced by DCPG.…”

“…Its EC 50 is ~1 μM (Duvoisin et al, 2010). DCPG was obtained from Tocris Bioscience (Ellisville, MO) and used at 1 μM, as previously (Quraishi et al, 2010). Its EC 50 is ~ 30 nM (Thomas et al, 2001).…”

“…Further, Higgs et al (2002) showed that L-AP4 modulated light-evoked OFF responses in ganglion cells, primarily by an effect on bipolar cell terminals. Finally, Quraishi et al (2010) found that DCPG reduced OFF ganglion cell light responses in mouse, suggesting that the effects observed by Awatramani and Slaughter (2001) and Higgs et al (2002) are at least partially mediated by mGluR8.…”

Selective activation of group III metabotropic glutamate receptor subtypes produces different patterns of γ‐aminobutyric acid immunoreactivity and glutamate release in the retina

“…For the mouse retina, it has been found that mGluR4, mGluR7, and mGluR8 are present in the inner plexiform layer (IPL), indicating their putative importance to inner retina processing (Quraishi et al,2007). A recent study has confirmed mGluR8 involvement in the modulation of ganglion cell electrophysiological responses to light stimulus (Quraishi et al,2010), but a study describing the effects of selective mGluR4, mGluR7, or mGluR8 activation or inhibition in retinal neurotransmitter release has never been conducted.…”