Our vision depends on two types of photoreceptors in the light-sensitive layer of eye called the retina. Rods photoreceptors detect photons at the lowest levels of light and support night vision, and cone photoreceptors sense bright light and discriminate between colors. Both rods and cones must wire into a neural circuit of the retina to send information to the brain.
Scientists have discovered how an auxiliary calcium channel subunit protein called α2δ4 establishes proper vision. Their research helps explain why mutations in the gene encoding α2δ4 lead to retinal dystrophy, a disease characterized by defective color vision and night blindness.
To study how this protein supports vision, the researchers modeled retinal dystrophy in mice. Like humans, mice lacking α2δ4 succumbed to the disease and their vision was compromised. The study was published in the journalNeuron.
In a previous study, the researchers identified a novel cell-adhesion protein called ELFN1 that rods use for making contacts with their partners, called bipolar neurons. However, how ELFN1 accomplishes the task of photoreceptor wiring was not clear.
In the new study, researchers showed that this connectivity requires α2δ4 to join a structure, called a higher order macromolecular complex, with ELFN1 and other proteins called calcium channels. These calcium channels trigger the release of the chemical messenger glutamate, which photoreceptors use for communicating with bipolar neurons.
In short, without both α2δ4 and the other calcium channels in the macromolecular complex, rods cannot connect to the neural circuit. "We found that α2δ4 is essential for organizing the presynaptic compartment of rod photoreceptors,"one of the authors said.
Strikingly, eliminating the corresponding gene for α2δ4 in a mouse model interrupted the transmission of light signals from photoreceptors to the brain without affecting the ability to detect light. "It's like you are trying to make a phone call--and your phone is fully functional--but you are not heard because there is no signal," senior author said.
Without the α2δ4, mice failed to see under dim light conditions and could not navigate a maze in low light due to their dysfunctional rods. Their cones were affected too, but they could still send some weak signals through to the brain.
"Their dim-light vision was completely abolished," said the senior author. "And the signal from the cones could barely make it."
Going forward, the team plan to study whether manipulating α2δ4 could help photoreceptors transmit their signals and maintain connectivity to stay functional longer in models of age-related vision loss, a major blinding condition in humans.
The researchers also think that wiring factors such as α2δ4 and ELFN1 could also help researchers address a current challenge in using stem cells to correct vision loss.