PirB: an immune system gene that restricts synaptic plasticity

From Carla Shatz’s lab at Harvard comes a paper describing the phenotype of paired-immunoglobulin like receptor-B (PirB) knockout mice.

Shatz was a student of David Hubel and Torsten Wiesel, who were both awarded the Nobel Prize in Physiology for their work on processing in the visual system. They showed that cells in the primary visual cortex responded to lines of a specific orientation, and, by depriving cats of sensory inputs from one eye, that ocular dominance columns devoted to a covered eye could, because of synaptic plasticity, receive inputs and process information from the other eye.

This study builds on this pioneering work. Shatz and her colleagues sutured one eye in their mice, thus stopping inputs entering the visual cortex on the opposite side. The other eye was exposed to green light.

The effect of this treatment was measured by looking at the expression patterns of Arc, a cytoskeleton-associated protein believed to play a role in stabilizing new connections. In the visual cortices of mice lacking PirB, the Arc expression domain was greatly expanded in comparison to normal mice.This suggests that increased plasticity had allowed for the formation of a greater number of new, experience-dependent connections in mice lacking the protein. Furthermore, greater plasticity was observed in immature mice lacking the protein than in wild type mice of the same age.

PirB is a major histocompatability complex I (MHCI) receptor; in situ hybridization was used to show that it is expressed throughout the brain in mice of all ages. In the immune system, major histocompatability proteins and their receptors (including PirB) are involved in presenting foreign proteins, or antigens, so that T-cells, which produce the immune response, can distinguish between self from non-self. PirB was thought to be active only in the immune system, but this study provides evidence that it also has an important role in the nervous system.

“Our study…reveals that at all ages, even during critical periods when circuits are prone to change, there are active molecular mechanisms that function to limit synaptic plasticity,” says Josh Syken, lead author of the forthcoming Science paper.

The findings can be extrapolated to the human brain, which generally becomes less plastic with age. Hence, the brain of a young child is far more plastic than that of an adult. This enables children to learn a language, for example, with far greater ease and in less time than an adult.

The findings could aid in the development of new treatments for stroke and other types of brain injury.

“By inhibiting the proteins that stop new connections growing, it may be possible for stroke victims to recover those missing links,” says Syken; however, he adds that, because humans may have up to 30 PirB alleles, such therapies may prove difficult to develop. Any such therapies could consequently lead to the use of combinations of PirB inhibitors and enhancers as memory enhancing ‘cogniceuticals’.

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