Immune Proteins Limit Brain Wiring

by Brenda Patoine

November, 2007

One of the biggest head-scratchers in modern neuroscience was the discovery in the past decade that certain immune-system molecules—previously not even thought to be present in the brain—are in fact all over the brain and apparently are critical to brain wiring and remodeling. At a packed symposium at the Society for Neuroscience meeting, a panel of researchers in this rapidly transforming field described how immune-signaling systems are being co-opted by the brain to prune and fine-tune its synapses.

During the past few years, researchers have found that the same molecules the immune system uses to defend against attack also affect normal brain function. Direct molecular communication between immune cells and brain cells seems to trigger dramatic changes in brain development, plasticity and repair. Armed with these new revelations, a few researchers are beginning to investigate how this cross-talk may be implicated in neurologic disorders.

The idea that the immune system is integral to one of the most fundamental and remarkable capacities of the nervous system—changes in the brain known as synaptic plasticity—bucks the long-standing conventional wisdom that these two systems do not play well together. The brain has always been considered “immune privileged”: immune cells that move freely through the rest of the body are off-limits or have only limited access to the brain thanks to a tight layer of cells and tissue called the blood-brain barrier. Even the brain’s specialized resident immune cells, microglia, can cause trouble if the response they trigger gets out of control and damages vulnerable neurons.

‘Smoking Gun’?

The latest chapter in neuroimmunology began with the surprise finding by Stanford neurobiologist Carla Shatz and her colleagues, then at the University of California-Berkeley, that a gene family known as major histocampatibility complex (MHC) class 1 molecules is very active during the development of the visual system. These molecules are part of the immune signaling system that allows T cells to recognize and destroy foreign or infected tissue.

The work, first reported in Neuron in 1998, shattered the accepted dogma about MHCs in the brain. Since then researchers focusing on MHCs and what they might be doing in the brain have replicated and expanded upon the finding.

For example, research by Alex Goddard in Shatz’s former lab at Harvard showed dramatic accumulations of MHC-1 molecules in the dendritic spines at the ends of nerve terminals, precisely at the points where one neuron connects with another via a synapse. In addition, two scientific posters at the Society for Neuroscience conference reported evidence for MHC-1s in neurons of the cerebellum and in the visual cortex.

“These molecules keep showing up in places of known synaptic plasticity,” Shatz said. “We think there’s a smoking gun here.”

Releasing the Brakes

In order to understand if there was a disruption in synapse wiring, Shatz and colleagues on her new Stanford lab team studied two variations of mice that had been genetically altered to lack functioning MHC-1 molecules. The mice turned out to have overzealous synaptic development in the visual system, which appeared to result from the failure of inappropriate synapses to be eliminated. The result was a disruption in the normally sharp segregation between neuronal pathways from the left and right eyes. There were also distinct abnormalities in synaptic plasticity in the hippocampus and cerebellum.

These changes persisted into adulthood, well beyond the transient developmental period during which synaptic remodeling is in hyper-drive. This suggests that MHC molecules, as a group, limit the extent of plasticity at all ages and might make an important contribution to regulating the known “critical periods” in brain development, including the decreased plasticity of adulthood and older age.

“As we get older, a kind of brake is put on our brain’s ability to change with experience, and MHCs seem to be part of this braking system,” Shatz said. “If we could find a way to release the brake, we might have a way to tune up the brain even beyond the normal window for doing so.”

Clues to Disease?

Lisa Boulanger, who collaborated with Shatz at Harvard and now runs her own lab at the University of California at San Diego, is also beginning to explore the disease implications of immune signaling in the brain. Her initial focus is on autism and schizophrenia.

“The discovery that immune proteins are ‘moonlighting’ in the brain raises the possibility that changes in the function of these proteins could affect both the immune system and brain development, which is exactly the combination we see in autism and schizophrenia,” Boulanger said.

In both conditions, immune abnormalities are common. In addition, population studies indicate that viral infections during the second trimester of pregnancy can increase the risk of having a baby with either autism or schizophrenia (genetic factors also play a role). Animal studies have added another key piece to the puzzle: When pregnant mice are infected with a virus, or even when their immune systems are activated chemically in the absence of a virus, their pups have brain and behavioral abnormalities that are reminiscent of some symptoms of autism and schizophrenia. This suggests that the immune response, rather than the virus, is the culprit.

“At this point we had to look deeper,” Boulanger said. “We already know that the levels of specific immune proteins, like MHC-1, are critical for normal development. So it’s possible that an immune response at the wrong time could change the levels of those proteins, right when they’re busy building the developing brain.”

 “We’re just beginning to look at the levels of these immune proteins in animal models of disease and in a few precious tissue samples from human patients,” she said. “But the fact that well-known immune proteins also participate in normal brain development and function opens up an exciting new area of research for many different neurological disorders.”