Pass the protein

Visual information from both eyes finally comes together when it is transmitted to the primary visual cortex. If one of the eyes is deprived of visual input during a ‘critical period’ of postnatal development, the representation of the non-deprived eye within the visual cortex expands at the expense of the deprived eye. This leads to a permanent loss of visual acuity (amblyopia) in the deprived eye.

The timing of this visual experience-dependent cortical plasticity requires a particular population of inhibitory interneurons within the visual cortex that express the marker parvalbumin (PV). Now, an international team of scientists, led by Takao Hensch at the RIKEN Brain Science Institute in Wako, has found that a protein called Otx2 is responsible for the final maturation of these cells (Fig. 1), and is therefore required for establishing the time during which visual cortex plasticity occurs¹.

Otx2 is a transcription factor, a type of protein that is involved in determining cell fate. Otx2 is expressed during embryonic development, and is necessary for formation of the head. Other groups had reported that Otx2 disappears from the rodent brain by postnatal day 13, but its presence at later points in development had not been examined. Surprisingly, Hensch and his colleagues found Otx2 protein re-emerging in the mouse brain by postnatal day 29. This re-appearance of Otx2 occurred within the sparse set of PV interneurons in parallel with the critical period of visual cortex plasticity.

The presence of Otx2 protein in the cortex required visual experience: when the researchers deprived mice of visual input by, for example, keeping them in the dark from birth, they observed a decrease in Otx2 and PV expression in the visual cortex. PV cell maturation is therefore dependent on visual experience during postnatal development.

Direct delivery of Otx2 protein into the visual cortex restored PV expression in visually deprived mice. Mature PV cells are encircled by extracellular matrix molecules that make up a peri-neuronal net (PNN) around the cell, and these PNNs do not form normally in mice that are kept in the dark. Delivery of Otx2 protein into the cortex was also sufficient to induce PNN formation around PV interneurons in visually deprived animals.

Mice normally open their eyes for the first time at postnatal day 13, but the critical period for visual cortex plasticity does not begin until at least a week later. The researchers found that infusion of Otx2 protein into the visual cortex of immature mice, at postnatal day 17, was able to shift the timing of the critical period for visual cortex plasticity to this earlier point in postnatal development (Fig. 2a). In addition, Otx2 infusion accelerated the maturation of the PV interneurons in the visual cortex.

Hensch and his colleagues then examined the visual cortex of mice that lacked Otx2. These Otx2-deficient mice had few PV-expressing cells and exhibited abnormal PNN development in their visual cortex, and did not show evidence of visual cortex plasticity (Fig. 2a).

Interestingly, even though Otx2 was required for the formation of the PV inhibitory interneurons, Otx2 was not produced within the cells that needed it. Instead, Otx2 was synthesized in distant structures involved in vision, such as the eye, and seemed to be transported to the cortex during visual activity (Fig. 2b): when the researchers injected a labeled Otx2 protein into the eye, they found that it showed up in the visual cortex within PV-expressing cells.

Hensch says that he and his colleagues “would like to visualize the transport process and to understand why these proteins are specifically attracted to PV cells in vivo. Both points will illuminate novel cell biology about how these classical molecules work.”