Researchers at KAIST have recently published biological research in Cell Reports. Photoreceptor release of glutamate in the dark is thought by a majority of people to be a resting state. However, to sense dark with the photoreceptors can damage biopolar cells in what is termed excitotoxicity. A group of bipolar cells, expressing AMPA and kainate glutamate receptors are depolarized by glutamate released from the photoreceptors in the dark. In their latest work, the researchers discovered a novel non-cell autonomous protective mechanism, provided by pre-synaptic partner photoreceptors, in bipolar cells.
Photosensation by vertebrate photoreceptor is a unique process in comparison to other sensory systems. Photoreceptors release an excitatory neurotransmitter glutamate in the dark, which a majority people believe to be a resting state, while they stop releasing it in the light. The glutamate then binds to its receptors in the post-synaptic membrane of bipolar cells. Upon the binding of glutamate to its receptors, a group of bipolar cells, which express AMPA and kainate glutamate receptors, are depolarized, while the other group of bipolar cells–which express metabotropic glutamate receptors (mGluR)–are hyperpolarized. The bipolar cells depolarized in the presence of light are classified as “ON-type”, whereas those depolarized in the dark are “OFF-type”. Since bipolar cells are connected to retinal ganglion cells (RGCs) that extend the axons to the brain to send visual information, combinatorial activation and inhibition of ON- and OFF-bipolar cell activity reflects the pattern of the light-activated photoreceptors to the brain via RGCs.
However, it is costly to sense light and dark with these retinal circuits. Prolonged exposure to the dark damage bipolar cells by the mechanism called as ‘excitotoxicity’. Excitotoxicity in the bipolar cells results from the extended increase of Ca2+ in the cells. To prevent from the excitotoxic state, bipolar cells develop various protective mechanisms in cell-autonomous and non-cell autonomous manners.
In their latest study, we discovered a non-cell autonomous protective mechanism, provided by their pre-synaptic partner photoreceptors, in bipolar cells. The protective factor released by the photoreceptor is the protein named as Otx2, which is captured by bipolar cells. The photoreceptor-derived Otx2 then move into the mitochondria to boost the synthesis of ATP, the cellular energy source used for various cellular events including cell survival. Therefore, with the absence or decrease of Otx2 supplementation from photoreceptors, the bipolar cells are prone to excitotoxicity. Indeed, it was the case of mice lost one copy of Otx2 gene. The amount of Otx2 synthesized in the photoreceptors dropped to half that of the normal level, as was the amount of Otx2 transferred to bipolar cells. It resulted in the progressive degeneration of the bipolar cells in the mice to lose the vision eventually. In the case of a human patient who lost one copy of the OTX2 gene, the first symptom was nyctalopia, night blindness, in childhood before the complete loss of vision. As the highlight of our research, the researchers found they could protect the mice from losing vision by a one-time injection of Otx2 protein directly into the mouse eyes. In the same sense, they hoped to prevent retinal degeneration and vision loss in human patients carrying OTX2 mutations.
As a surprise to everyone, Otx2 has been known well as a transcription factor that controls the development of head and brain by inducing gene expression. Beyond the conventional function in the nucleus, the researchers also have discovered an unconventional trafficking of homeodomain-containing transcription factors including Otx2 in mouse nervous tissues. However, the physiological relevance of the trafficking is, up till now, not fully understood. In this study, the researchers provide one but very intriguing example. Since there are more than 200 homeodomain transcription factors in human, they believe there should be additional proteins that play similar protective roles in other tissues. They are now moving in the direction of discovery of those!
* Laboratory website : http://bs.kaist.ac.kr/~neurodev/Home.html