Professor Carla Shatz of Stanford University and her colleagues have discovered a way to revert an adult brain to the “plastic”, child-like state that is more able to form new connections quickly. The technical term “plastic” implies the ability to adapt or shape itself to new conditions. The striking results were revealed through experiments on a protein expressed in brain cells known as PirB (this is the name of the protein in the animal model, in humans it is called “LilrB2″), which seems to stabilize neural connections.
Stability protects against loss of learned skills or information, but at the same time hampers the acquisition of new ones. The scientists found that interfering with the normal function of the neuron-stability molecule PirB had the remarkable effect of reverting at least one part of the brain to a more malleable state that could easily recover from damage, rewire itself and learn new skills. The study is exciting for not only its therapeutic implications, but also for the emerging field of brain and cognition-enhancing drugs.
The scientists worked in a model animal and disrupted the regular function of a receptor called PirB. The receptor, which is also found in humans, was removed from the visual cortex specifically by either acute shut-down of its gene using genetic engineering tools or repression of its function with a drug. When the animals were forced to use one eye (thus mimicking “amblyopia”, or “lazy eye” in common parlance), the neural circuits of the visual centers of the brain rewired better to the remaining good eye compared to animals for which the PirB molecule was not suppressed. The results held true in the adult animal, not just during the critical development period when the brain is naturally extremely plastic.
The strategy of disrupting PirB holds true not only for the specific case of lazy eye, but also for other types of neural pathologies, including those that arise from acute injuries such as strokes. Interestingly, the PirB molecule seems to be involved in immunity although it was found, at least in the mouse, to be expressed throughout the brain in mice regardless of age. Prior experiments show that the human version, LilrB2, may play a role in Alzheimers disease. Scientists have found that amyloid beta, a protein that is highly abundant in brains of patients with Alzheimers, binds to the LilrB2 protein. In animal experiments the binding leads to loss of synaptic plasticity.
The molecule used in this study to interfere with and diminish the effect of PirB was a soluble “ectodomain” of PirB. Since PirB is a receptor molecule, flooding it into the bloodstream or an organism, whether animal or human, should have the effect of “soaking” up the natural target or ligand molecule which drives the activity of the pathway. A genetic method was also used to turn off the receptor at different points of development in the animal.
One challenge remains in the targeting of LilrB2 in humans. Humans have 5 similar variants named LilrB1 through LilrB5. Disruption may be required in more than one of the proteins.
Dr. David Bochner and Richard Sapp contributed equally as primary authors.
The research was published on Oct 15, 2014 in Science Translational Medicine.