A Novel Connection between Rods and ON Cone Bipolar Cells Revealed by Ectopic Metabotropic Glutamate Receptor 7 (mGluR7) in mGluR6-Deficient Mouse Retinas

Tsukamoto, Yoshihiko; Morigiwa, Katsuko; Ishii, Masaaki; Takao, Motoharu; Iwatsuki, Ken; Nakanishi, Shigetada; Fukuda, Yutaka

doi:10.1523/jneurosci.5646-06.2007

Cited by 55 publications

(63 citation statements)

References 27 publications

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“…In addition to the tertiary rod-HBC C pathway proposed by previous studies (13,33,35), our data suggest direct rod-DBC C1 and direct cone-DBC R2 tertiary pathways in the mouse retina. Recent electron microscopic studies reveal chemical synapses made from mouse rods to DBC C s (20), and our data suggest that these synapses are functional and responsible for a substantial share of the DBCs' photoreceptor inputs. Although no ultrastructural evidence is available for direct chemical synapses from cones to DBC R s, we clearly show significant cone inputs to DBC R2 s (wild-type mouse results in Fig.…”

Section: Discussionsupporting

confidence: 54%

“…Studies on normal and coneless transgenic mice and rabbits indicate that rods send signals directly to certain types of HBCs (13,18). Moreover, recent electron microscopic analysis suggests that rods in the mouse retina make chemical synapses on some HBC C s and DBC C s (19,20). These results suggest that functional pathways mediating DBC and HBC responses in mammalian retinas may be more complex than the general plan set forth by earlier anatomical studies.…”

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confidence: 97%

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Direct rod input to cone BCs and direct cone input to rod BCs challenge the traditional view of mammalian BC circuitry

Pang

Gao

Lem

et al. 2009

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

132

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Bipolar cells are the central neurons of the retina that transmit visual signals from rod and cone photoreceptors to third-order neurons in the inner retina and the brain. A dogma set forth by early anatomical studies is that bipolar cells in mammalian retinas receive segregated rod/cone synaptic inputs (either from rods or from cones), and here, we present evidence that challenges this traditional view. By analyzing light-evoked cation currents from morphologically identified depolarizing bipolar cells (DBCs) in the wild-type and three pathway-specific knockout mice (rod transducin knockout [Trα], and transcription factor beta4 knockout [Bhlhb4, we show that a subpopulation of rod DBCs (DBC R2 s) receives substantial input directly from cones and a subpopulation of cone DBCs (DBC C1 s) receives substantial input directly from rods. These results provide evidence of the existence of functional rod-DBC C and cone-DBC R synaptic pathways in the mouse retina as well as the previously proposed rod hyperpolarizing bipolar-cells pathway. This is grounds for revising the mammalian rod/cone bipolar cell dogma.light-evoked cation and chloride currents | axon-terminal stratification | connexin36 | wild-type and mutant mice | depolarizing bipolar cell I n the visual system, rod photoreceptors register dim light signals, and cone photoreceptors encode brighter light signals (1). Bipolar cells (BCs) are the second-order neurons in the retina that receive light-elicited signals from rod and cone photoreceptors and transmit them to amacrine cells (ACs) and ganglion cells (GCs) in the inner retina (1, 2). Early anatomical studies have shown that mammalian rods make synaptic contacts with only one type of bipolar cell, the rod depolarizing bipolar cell (DBC R ), whereas cones make synaptic contacts with eight to nine types of cone depolarizing (DBC C s) or hyperpolarizing bipolar cells (HBC C s) (3-5). Additionally, DBC R s do not make output synapses directly on GCs, the output neurons of the retina, but on the AII amacrine cells (AIIACs), which make electrical synapses (with connexin36 at least at the AIIAC side) (6, 7) with DBC C s (that send signals to ON GCs) and inhibitory glycinergic synapses with HBC C s and OFF GCs (8-10). Therefore, in addition to direct cone synaptic inputs, DBC C s receive rod-mediated signals from AIIAC-DBC C electrical synapses, and HBC C s receive rod-mediated signals from the AIIAC-HBC C chemical synapses (11,12). This AIIAC-mediated rod/cone signal mixing is named the primary rod-to-cone signaling pathway (13). Furthermore, rods and cones are electrically coupled with each other, possibly through connexin36-mediated gap junctions (6,14,15), and such rod/cone-signal mixing at the photoreceptor level is named the secondary rod-cone pathway (13).The rod and cone bipolar cell-signaling circuitry described above has been considered for many years as the general organizational plan (to a certain degree as the dogma) for all mammals (3,5,16). Evidence from recent studies, however, begins to challenge t...

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Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 97%

Direct rod input to cone BCs and direct cone input to rod BCs challenge the traditional view of mammalian BC circuitry

Pang

Gao

Lem

et al. 2009

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

132

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“…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 1994;Kikkawa et al 1993;Masu et al 1995;Vardi and Morigiwa 1997), this activates the G protein G o (Dhingra et al 2002;Dhingra et al 2000;Okawa et al 2010;Vardi et al 1993), and this in turn leads to closure of a presumably constitutively active nonselective cation channel, recently identified as transient receptor potential melastatin 1 (TRPM1) (Koike et al 2010b;Morgans et al 2009). Mutations of this channel in humans lead to night blindness (Audo et al 2009;Li et al 2009;Nakamura et al 2010;van Genderen et al 2009). …”

mentioning

confidence: 99%

“…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.…”

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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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“…At least 11 distinct bipolar cell types have been characterized in the mouse retina based on morphological criteria (Ghosh et al, 2004) and the expression of cell-type-specific markers (Haverkamp et al, , 2008Mataruga et al, 2007). Bipolar cells are also classified by their response to glutamate as either OFF (types 1-4) or ON (types 5-9 and rod bipolar cells; Schiller, 1992;Masu et al, 1995;Euler et al, 1996;Hartveit, 1997;DeVries, 2000;Ghosh et al, 2004) and by their distinct synaptic connections with rod and/or cone photoreceptors (Sharpe and Stockman, 1999;Tsukamoto et al, 2001Tsukamoto et al, , 2007Mataruga et al, 2007;Haverkamp et al, 2008). Little is known, however, about the mechanisms that underlie the formation of the distinct bipolar cell types.…”

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confidence: 99%

Requirement for the paired‐like homeodomain transcription factor VSX1 in type 3a mouse retinal bipolar cell terminal differentiation

Shi¹,

Jervis²,

Nickerson³

et al. 2011

J of Comparative Neurology

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Retinal bipolar cells make up a class of at least 11 distinct interneurons that have been classified through morphological and molecular approaches. Previous work has shown that the paired-like homeodomain transcription factor Vsx1 is essential for the proper development of a subset of these interneurons. In Vsx1-null mice, bipolar cells are properly specified but exhibit terminal differentiation defects characterized by reduced expression of OFF bipolar cell markers and defects in OFF visual signaling. Here, we further examined the role of Vsx1 in OFF bipolar cells using recently identified cell-type-specific markers. In contrast to its previously characterized expression in type 2 OFF bipolar cells, Vsx1 expression was not detected in type 3 OFF bipolar cells, by either immunohistological or transgenic reporter labeling approaches. This observation was unexpected given previous findings that Cabp5 immunolabeling of type 3 bipolar cell axon terminals is reduced in Vsx1-null mice. However, we observed reduced levels of the type 3a bipolar cell marker hyperpolarization-activated and cyclic nucleotide-gated channel 4 (HCN4) in Vsx1-null mice, which is consistent with a requirement for Vsx1 in type 3 bipolar cell differentiation. In contrast, expression of the type 3b bipolar cell marker regulatory subunit RII-beta of protein kinase A was unchanged. Despite the absence of Vsx1 in mature type 3 bipolar cells, colabeling of Vsx1 and HCN4 was observed at postnatal stages. These findings reveal a role for Vsx1 in type 3a bipolar cells and suggest that Vsx1 function is required transiently in this cell type during the postnatal period.

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A Novel Connection between Rods and ON Cone Bipolar Cells Revealed by Ectopic Metabotropic Glutamate Receptor 7 (mGluR7) in mGluR6-Deficient Mouse Retinas

Cited by 55 publications

References 27 publications

Direct rod input to cone BCs and direct cone input to rod BCs challenge the traditional view of mammalian BC circuitry

Direct rod input to cone BCs and direct cone input to rod BCs challenge the traditional view of mammalian BC circuitry

mGluR6 deletion renders the TRPM1 channel in retina inactive

Requirement for the paired‐like homeodomain transcription factor VSX1 in type 3a mouse retinal bipolar cell terminal differentiation

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