Abstract
Müller cells maintain retinal synaptic homeostasis by taking up glutamate from the synaptic cleft and transporting glutamine back to the neurons. To study the interaction between Müller cells and photoreceptors, we injected either DL-α-aminoadipate or L-methionine sulfoximine–both inhibitors of glutamine synthetase–subretinally in rats. Following injection, the a-wave of the electroretinogram (ERG) was attenuated, and metabotropic glutamate receptor 5 (mGluR5) was activated. Selective antagonism of mGluR5 by 2-methyl-6-(phenylethynyl)-pyridine increased the ERG a-wave amplitude and also increased rhodopsin expression. Conversely, activation of mGluR5 by the agonist, (R,S)-2-chloro-5-hydroxyphenylglycine, decreased both the a-wave amplitude and rhodopsin expression, but upregulated expression of Gq alpha subunit and phospholipase C βIII. Overexpression of mGluR5 reduced the inward-rectifying potassium ion channel (Kir) current and decreased the expression of Kir4.1 and aquaporin-4 (AQP4). Further experiments indicated that mGluR5 formed a macromolecular complex with these two membrane channels. Lastly, increased expression of mGluR5 was found in Royal College of Surgeons rats–a model of retinitis pigmentosa (RP). Inhibition of mGluR5 in this model restored the amplitude of ERG features, and reduced the expression of glial fibrillary acidic protein. These results suggest that mGluR5 may be worth considering as a potential therapeutic target in RP.
Highlights
Photoreceptor degeneration is poorly understood, but can lead to blindness in retinitis pigmentosa (RP)
We found that AQP4 and Kir4.1 co-immunoprecipitated with metabotropic glutamate receptor 5 (mGluR5) (Fig. 7D), suggesting that mGluR5 does directly interact with AQP4/Kir4.1 molecules in Müller cells
To ensure that we were effectively inhibiting Müller cells, we examined the effects of various concentrations (7, 70 and 140 μg/μl) of DL-AAA on the ERG (Fig. S5)
Summary
Photoreceptor degeneration is poorly understood, but can lead to blindness in retinitis pigmentosa (RP). The role of Müller cells includes the uptake and recycling of glutamate released by photoreceptors[2]. The proper function of the glutamatergic synapse is dependent on presynaptic release machinery and postsynaptic receptors, and on the effective removal of glutamate from the synaptic cleft ( preventing neuronal excitotoxicity). Glutamate is taken up by Müller cells via excitatory amino acid transporter 1 (EAAT1, known as glutamate/aspartate transporter [GLAST]) and is converted into glutamine by glutamine synthetase (GS), which is a glia-specific enzyme[1, 13], and transported back to the neurons for recycling into glutamate. Despite its minority role at the synapse, the inhibition of EAAT1 still affects the retinal response to light, causing a reduction in the amplitude of the scotopic electroretinogram (ERG) b-wave[14,15,16], which suggests an effect www.nature.com/scientificreports/. The selective ablation of Müller cells results in apoptosis of the photoreceptors, and in decreased amplitudes of both a- and b-waves in the ERG24, 25
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