Impairment of Pupillary Responses and Optokinetic Nystagmus in the mGluR6-deficient Mouse

Iwakabe, Hideki; Katsuura, Goro; Ishibashi, Chiyomi; Nakanishi, Shigetada

doi:10.1016/s0028-3908(96)00167-0

Cited by 57 publications

(58 citation statements)

References 34 publications

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“…We used behavioural tests that measure the integrity of the outer retina (electroretinograms) 23 , eye tracking functions (optokinetic nystagmus) 24 , visual acuity (optomotor) 25 , object identification (water maze) 26 , pupil constriction (PLR) 8,12 , the period of the circadian oscillator (wheel running activity) 10,11 , the adjustment of the circadian clock to different light stimulations (circadian photoentrainment, phase shifting, and constant light) 10,11 and direct light effects on activity (masking) 9 .…”

Section: Behavioural Analysesmentioning

confidence: 99%

Melanopsin cells are the principal conduits for rod–cone input to non-image-forming vision

Güler

Ecker

Lall

et al. 2008

Nature

767

686

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Rod and cone photoreceptors detect light and relay this information through a multisynaptic pathway to the brain via retinal ganglion cells (RGCs) 1 . These retinal outputs support not only pattern vision, but also non-image forming (NIF) functions, which include circadian photoentrainment and pupillary light reflex (PLR). In mammals, NIF functions are mediated by rods, cones and the melanopsincontaining intrinsically photosensitive retinal ganglion cells (ipRGCs) 2, 3 . Rod/cone photoreceptors and ipRGCs are complementary in signalling light intensity for NIF functions 4-12 . The ipRGCs, in addition to being directly photosensitive, also receive synaptic input from rod/cone networks 13, 14 . To determine how the ipRGCs relay rod/cone light information for both image and non-image forming functions, we genetically ablated ipRGCs in mice. Here we show that animals lacking ipRGCs retain pattern vision, but have deficits in both PLR and circadian photoentrainment that are more extensive than those observed in melanopsin knockouts 8,10,11 . The defects in PLR and photoentrainment resemble those observed in animals that lack phototransduction in all three †To whom correspondence should be addressed.

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Section: Behavioural Analysesmentioning

confidence: 99%

Melanopsin cells are the principal conduits for rod–cone input to non-image-forming vision

Güler

Ecker

Lall

et al. 2008

Nature

767

686

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“…The mice had normal light-conditioned behavioral responses (i.e., avoidance of a shock preceded by a light) (15) and normal circadian locomotor activity. However, they had no pupillary responses to dim light and had reduced and delayed pupillary responses to bright light (16). Also, optokinetic responses were diminished especially to low-contrast stimuli (16).…”

mentioning

confidence: 93%

“…However, they had no pupillary responses to dim light and had reduced and delayed pupillary responses to bright light (16). Also, optokinetic responses were diminished especially to low-contrast stimuli (16). We undertook this study to identify humans with similar loss-of-function mutations in the homologous human gene and to document their visual function.…”

mentioning

confidence: 99%

Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6

Dryja

McGee²,

Berson³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

225

175

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We report three unrelated patients with mutations in the GRM6 gene that normally encodes the glutamate receptor mGluR6. This neurotransmitter receptor has been shown previously to be present only in the synapses of the ON bipolar cell dendrites, and it mediates synaptic transmission from rod and cone photoreceptors to this type of second-order neuron. Despite the synaptic defect, best visual acuities were normal or only moderately reduced (20͞15 to 20͞40). The patients were night blind from an early age, and when maximally dark-adapted, they could perceive lights only with an intensity equal to or slightly dimmer than that normally detected by the cone system (i.e., 2-3 log units above normal). Electroretinograms (ERGs) in response to single brief flashes of light had clearly detectable a-waves, which are derived from photoreceptors, and greatly reduced b-waves, which are derived from the second-order inner retinal neurons. ERGs in response to sawtooth flickering light indicated a markedly reduced ON response and a nearly normal OFF response. There was no subjective delay in the perception of suddenly appearing white vs. black objects on a gray background. These patients exemplify a previously unrecognized, autosomal recessive form of congenital night blindness associated with a negative ERG waveform. bipolar cell ͉ glutamate receptor ͉ retina

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“…The general structure of the retina and the ON bipolar cells appears normal (Masu et al 1995;Tagawa et al 1999), although ectopic ribbons and mislocalization of mGluR7 have been seen in ON cone bipolar cells Tsukamoto et al 2007). The visual ON pathway, as revealed by electroretinogram, certain behavioral tasks (Takao et al 2000), pupillary responses, and optokinetic nystagmus (Iwakabe et al 1997), is impaired. However, a late ON response is still observed in superior colliculus (Sugihara et al 1997) and ganglion cells (Renteria et al 2006), a feature that may explain why both mGluR6-null and wild-type (WT) mice respond similarly to light increments in an avoidance test (Masu et al 1995).…”

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confidence: 99%

mGluR6 deletion renders the TRPM1 channel in retina inactive

Dhingra

Fina

et al. 2012

Journal of Neurophysiology

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In darkness, glutamate released from photoreceptors activates the metabotropic glutamate receptor 6 (mGluR6) on retinal ON bipolar cells. This activates the G protein G o , which then closes transient receptor potential melastatin 1 (TRPM1) channels, leading to cells' hyperpolarization. It has been generally assumed that deleting mGluR6 would render the cascade inactive and the ON bipolar cells constitutively depolarized. Here we show that the rod bipolar cells in mGluR6-null mice were hyperpolarized. The slope conductance of the current-voltage curves and the current noise were smaller than in wild type. Furthermore, while in wild-type rod bipolar cells, TRPM1 could be activated by local application of capsaicin; in null cells, it did not. These results suggest that the TRPM1 channel in mGluR6-null rod bipolar cells is inactive. To explore the reason for this lack of activity, we tested if mGluR6 deletion affected expression of cascade components. Immunostaining for G protein subunit candidates G␣ o , G␤ 3 , and G␥ 13 showed no significant changes in their expression or distribution. Immunostaining for TRPM1 in the dendritic tips was greatly reduced, but the channel was still present in the soma and primary dendrites of mGluR6-null bipolar cells, where a certain fraction of TRPM1 appears to localize to the plasma membrane. Consequently, the lack of TRPM1 activity in the null retina is unlikely to be due to failure of the channels to localize to the plasma membrane. We speculate that, to be constitutively active, TRPM1 channels in ON bipolar cells have to be in a complex, or perhaps require an unidentified factor. rod bipolar; metabotropic glutamate receptor 6-null; G protein cascade; transient receptor potential melastatin 1; regulator of G protein signaling IN RETINA, AN INCREMENT OF light intensity hyperpolarizes the photoreceptor and sets off two opposing signals in the OFF and ON bipolar cells. In darkness, glutamate released by photoreceptors depolarizes OFF bipolar cells and hyperpolarizes ON bipolar cells. The key steps in this ON bipolar cell "sign inverting" cascade are as follows: glutamate activates the metabotropic glutamate receptor 6 (mGluR6) (Akazawa et al.

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Impairment of Pupillary Responses and Optokinetic Nystagmus in the mGluR6-deficient Mouse

Cited by 57 publications

References 34 publications

Melanopsin cells are the principal conduits for rod–cone input to non-image-forming vision

Melanopsin cells are the principal conduits for rod–cone input to non-image-forming vision

Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6

mGluR6 deletion renders the TRPM1 channel in retina inactive

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