"Plasticity Pill" Could Rewire Brain to Treat Autism and Schizophrenia

Super-mice bred to lack certain immune molecules display a superior ability to form new neural connections, or strengthen existing ones — and they could serve as a model for reversing brain disease.

Somewhere on the campus of Stanford University, among the stately oaks and tile-roofed temples of scientific inquiry, live Carla Shatz’s super-mice. They learn complex physical tasks more quickly than their ordinary cousins. If one eye is deprived of sight, they rapidly rewire their brains to compensate, then beat normal one-eyed mice on tests of visual acuity. They recover more readily from some brain injuries, too. What sets these rodents apart is their superior ability to form new neural connections, or strengthen existing ones, in response to experience.

Shatz is proud of her prodigies. But when I ask for permission to visit them, the pioneering neurobiologist turns me down. “They’re in a germ-free facility,” she says apologetically, glancing away from a video in which a tiny champion powers through a water maze. Only their handlers are allowed into the lab where the animals are kept, Shatz explains, and even they must shower and don sterile garments before entering. That’s because the mice have incomplete immune systems. They’ve been bred to lack proteins — members of a family called MHCI (which stands for major histocompatibility complex class I) — crucial to fighting pathogens. The same mutation that gives them their supremely adaptive brains has left them with extraordinarily vulnerable bodies.

In the body, MHCI proteins are watchdogs, tagging infected cells for immune attack. In the brain, these proteins assume an entirely different role, helping to regulate neuroplasticity — the ability of neural circuits to reshape themselves at every stage of life. Shatz has spent more than a decade probing the latter function. Yet until she proved otherwise, few scientists thought MHCI or other so-called “immune molecules” were even present in a normally functioning brain. In fact, their absence was a basic tenet of neuroscience.

As you may recall from biology class, the brain enjoys what’s known as immune privileged status. A dense layer of cells called the blood-brain barrier protects the organ from germs circulating in the body, and from the immune cells that combat them. That is why, when you are battling the flu, neither the virus nor the inflammation directed against it spreads into your delicate cerebral neurons. Unless the barrier is breached by injury, autoimmune disease or catastrophic infection, rarely does a T cell, a B cell or any of the immune system’s other shock troops get through. It was long believed that the immune system’s molecular sentinels — molecules like MHCI — were missing from within the brain, too. 

Then, 15 years ago, Shatz stumbled across genes coding for MHCI in fetal cat brains. She soon unearthed MHCI proteins and receptors (molecules that bind with MHCI) in the unimpaired noggins of mice. They eventually turned up in healthy monkey and human brains as well. And as Shatz devoted herself to investigating MHCI and its entourage in those surprising places, she sparked a neuroscientific revolution.

Today, a growing number of researchers are examining the complex ways in which immune molecules affect the brain and nervous system. Manipulating such molecules, these scientists believe, may be key to treating many devastating neurological ailments, from autism and schizophrenia to Alzheimer’s and ALS. Shatz even dreams of a “plasticity pill” to restore the neural suppleness of stroke victims — and her latest experiments offer hope that it could someday come to pass. 

“People thought we were crazy when we made this discovery,” says Shatz, a slender 66-year-old with high cheekbones and a halo of dark curls. “But my parents gave me some advice when I was young. They said, ‘Don’t worry about what other people think of you.’ ” She gazes pensively at the computer screen. “I probably generalized it too much.”

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