Session 4-1

Impaired transmission from photoreceptors to bipolar cells: mouse models

Neal S. Peachey Cole Eye Institute, ClevelandClinic Foundation, Cleveland, Ohio, USA Research Service,Cleveland VA Medical Center, Cleveland, Ohio, USA

In response to light, photoreceptors normally decrease the rate of glutamate release at their terminal. This change is detected by two classes of bipolar cells, which are distinguished by whether they depolarize (DBCs) or hyperpolarize (HBCs) in response to light. The

electroretinogram (ERG) can be used to monitor this process as the ERG a-wave reflects photoreceptor activity while the b-wave is generated by bipolar cell responses. As a consequence, a selective reduction in the ERG b-wave is usually indicative of a defect in transmission between photoreceptors and bipolar cells. This situation is encountered in

naturally occurring and genetically engineered mice, the study of which shed light on the

development and maintenance of the photoreceptor-to-bipolar cell synaptic process. For

example, null in the encoding mGluR6 or G• 0 eliminate the b-wave and

confirm the role of these in DBC signal transduction. A similar ERG pattern is seen

in the nob (no b-wave) mouse, which is caused by a defect in nyx, encoding nyctalopin.

Although the precise function of nyctalopin is unknown, the localization of nyctalopin

transcripts to the outer nuclear layer indicates that this may play a critical role in the

DBC response. Despite the lack of DBC function, ribbon synapses form normally in nob mice.

Presynaptically, glutamate release is controlled by L-type calcium channels located on the

photoreceptor terminal. The b-wave is selectively reduced in CNS• 2-null mice, lacking the

•2 subunit of the L-type calcium channel in the central nervous system. In addition, the

normal distribution of the pore-forming • 1F subunit is markedly disturbed, indicating that the

• 2 subunit is required to guide the formation of a functional channel. Such channels are likely

to be required for ribbon synapse formation, as ribbon structures are rarely encountered in

CNS• 2-null mice. As the nob and CNS• 2-null mice involve genes that underlie two forms of

congenital stationary night blindness, study of these animal models will expand our

understanding of these rare human disorders.

Keywords: mouse, electroretinogram, retina

21 Session 4-2

Selective dysfunction of On and/or Off-bipolar cell in human diseases

Yozo Miyake, Mineo Kondo, Makoto Nakamura and Hiroko Terasaki Departmentof Ophthalmology,Nagoya UniversitySchool of Medicine,Nagoya, Japan

In human, cone visual signals in the retina are processed through dual pathways, one involving ON-center bipolar cells (ON-pathway) and the other through OFF-center bipolar

cells (the OFF-pathway), while rod visual signal is processed only through ON-pathway.

Little is known about how the patients can see when ON and/or OFF-pathway are defective

selectively. By comparing the monkey's ERG (electroretinogram) blocked ON- or

OFF-pathway using glutamate neurotransmitter analogs, we have detected new clinical

entities in human where ON- and/or OFF-pathway are blocked in both rod and cone visual

pathways. We hypothesized that complete type congenital stationary night blindness (CSNB

1) can be a model disease having a complete dysfunction of only ON-pathway, while

incomplete type (CSNB 2) has an incomplete dysfunction of both ON and OFF-pathway in

both rod and cone visual systems. The was detected in nyctalopin in CSNB 1,

and in L-type calcium channel ƒ¿l subunit in CSNB 2.

We analyzed 90 patients (49 patients with CSNB 1, 41 patients with CSNB 2) in terms of

scotopic vision (dark adaptation) and photopic vision (visual acuity, contrast sensitivity and

color vision). The scotopic vision was found to be impaired completely and incompletely in

CSNB 1 and CSNB 2, respectively. The photopic visions are better preserved than we

expected even when the full-field photopic ERG showed complete defect of ON-visual

pathway. Judging from the findings of focal macular cone ERG, we found that the macula of

these patients is selectively spared from the generalized defect of entire retina.

Keywords: bipolar cell dysfunction, ERG, psychophysical function

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