Main content

    Californi Pacific Currents 2002

    Currents 2002 Table of Contents | Currents Main Page

    Neuroreceptor Research Hints at Protective Therapy for Brain Injury

    Most of our thoughts and actions are driven by memory, that shadowy hard-drive residing somewhere amid the web of connections in the billions of neurons in our brain. (A neuron is a nerve cell that transmits electrical impulses.) Researchers tell us that each connection in this delicate web is formed when one neuron releases a special chemical across a gap, or synapse, to bind to a receptor of a receiving neuron. Thus, these receptors are the “glue” that holds the web of neurons — and our sense of self — together.

    That’s the kind of Nova-style summary that routinely boggles and excites the mind of the nonscientist. For Eric Beattie, PhD, one of the newest associate scientists at California Pacific Medical Center Research Institute, it’s more a statement of job security and satisfaction and essentially guarantees that every day he spends as a neuroscientist will be “a brand new day.”

    “The more you learn about the incredible complexity and subtly of the brain,” he says, “the more you feel we’re never going to know the entire story. However, this is an especially exciting time to be in neuroscience because we’re learning enough to make some very practical in-roads into the complexities of the brain in health and disease.”

    Dr. Beattie is now pursuing several highly practical avenues of research related to the receptors on neurons, or “neuroreceptors” in the brain. The foundation for this research was built on his thesis project with Bill Mobley, now at Stanford, involving the role of nerve growth factor receptors in neuron development and maintenance. Then, in collaboration with postdoctoral advisors Rob Malenka at Stanford University and Mark von Zastrow at UCSF, Beattie helped show that the strength of neuron-to-neuron connections depends on the number of specialized receptors (abbreviated as AMPARs) studding the neuron surface. A chemical called glutamate is the major neurotransmitter in the central region of the brain, called the hippocampus, which is the focus of Beattie’s research.

    “The hippocampus doesn’t really store all the memories,” explains Dr. Beattie, “but it is involved in the setting down and retrieval of memories. “It's like a computer’s file management program, with memories flowing through it and then being distributed and stored in separate ‘files’ all across the brain.” He also points out that the hippocampus is the area targeted by neurodegenerative diseases such as Alzheimer’s.

    Beattie and his mentors at UCSF and Stanford described a simple mechanism by which neurons in a critical region of the brain could increase or decrease their sensitivity. More AMPARs at the surface led to greater connectivity. Fewer surface receptors meant fewer neurons firing. What’s more, the AMPARs descended from the surface to a storage area below the surface in a matter of minutes. All this provided an elegant explanation for the rapid modulation of neuron-to-neuron communication and quite possibly for how the brain retains its plasticity — that is, it’s ability to “re-wire” its memory as it constantly learns, re-learns, blocks out, recalls in a rosy light, and generally adapts and responds to the ups and downs of life.

    A Brother’s Clue
    For years, it has been known that synaptic pathways can be strengthened by the neuronal activities associated with memory formation. Conversely, the low level of neuronal activity seen when no memory process is engaged can weaken the synapses — a classic use-it-or-lose-it scenario. But if surface AMPARs help to control synaptic strength, as shown by Beattie et al., then what might control the minute-to-minute movement of AMPARs at the surface?

    This was the natural follow-up question that occurred not only to Eric Beattie but to his older brother Michael, who happens to be chairman of neurosciences at Ohio State University.

    “He actually read my paper and called me!” exclaims the younger Beattie, who says he was first bitten by the science bug working as a high school summer intern in his brother’s Ohio research lab. But despite their shared professional interests, the two hadn’t actually collaborated on much scientifically in the past 20 years despite carving the annual Thanksgiving turkey.

    For all those years, it turns out, the elder Beattie and his wife Jacqueline Bresnahan (also a neuroscientist) had specialized in mapping the chemical changes that follow spinal cord injury. A few years ago, they discovered that a huge rise in a natural inflammation-related chemical called tumor necrosis factor alpha (TNFa) was associated with the death of neurons in the spinal cord. Usually thought of as an inflammatory molecule involved in scavenging and clean-up after cell damage, TNFa was now implicated in spinal cord injury. Even more interesting was the Ohio couple’s demonstration that the neuronal damage associated with TNFa was enhanced by glutamate overstimulation. For example, if you blocked glutamate receptors after injury, you could block the expected death of neurons.

    Based on these serendipitous clues, Beattie quickly brought together his old collaborators from Stanford and UCSF with his new ones in Ohio to see if TNFa could be another important traffic cop for AMPARs. As the potential source of TNFa, they focused on the glial cells that encase neurons throughout the central nervous system.

    Yes, TNFa Controls Synaptic Strength
    As reported in their 2002 Science paper, the group showed that TNFa did indeed control AMPAR surface levels and synaptic strength. Specifically, they documented that changing the presence or activity of TNFa in various rat brain models changed the number of AMPARs on the neuron surface and also the amount of synaptic transmission in those cells.

    With these findings, a potential chain of events leading to permanent neuronal damage following brain injury suddenly fell into place. Whether the trauma was due to stroke, spinal cord injury, blunt trauma, or even to slower disease like Alzheimer’s or Parkinson’s, Beattie explains that the cascade of events might go something like this: (1) trauma occurs to the CNS, (2) glial cells release too much TNFa, (3) neurons bring too many AMPARs to the surface, (4) the neuron is overstimulated, and (5) cell death is triggered.

    “TNFa is a protein,” says Dr. Beattie, “that we think is normally pumped out at low levels by glial cells, helping to modulate the strength of the neuron-to-neuron connections. But in injury situations, TNFa is overproduced and it overloads the system. This is exciting but also very complex. You need the AMPARs at the cell surface in appropriate amounts for proper synaptic strength and neuron-to-neuron communication, but too much can lead to cell death. It’s not black and white. You need a balance.”

    Clinical Implications
    The next step for Beattie, and the mission of his new laboratory at California Pacific, is to find out exactly how TNFa causes AMPARs and possibly other neuroreceptors to pop up on the neuronal surface at synapses. As part of this effort, he is also looking for ways to control this short-term surge in AMPAR receptor display following CNS trauma. In fact, he and his colleagues have applied for a patent for this treatment strategy using both existing and proprietary compounds. He points out that other researchers are developing therapies to protect neurons after injury — such as TNFa receptors to soak up the overload of this molecule — but his group will remain focused on the neuroreceptor itself.

    “If you can slow down AMPAR activity following injury,” Dr. Beattie says, “maybe you can protect cells during that time the neuron is going haywire because of the increased TNFa. If we can understand the system and protect people with the most drastic injuries — those with spinal cord or brain trauma, stroke, epilepsy, or Alzheimer’s — then this will be a huge step forward.”

    But what about those of us simply wanting to recall the name of that actor (whose last name starts with a “B”?) in that movie we saw last month? Or polish off the Friday crossword? Beattie says don’t hold your breath. “The more I learn about the system,” he says, “the more I appreciate its delicacy and subtlety. Dumping drugs on it to fine-tune the memory, to tweak up the surface receptors by 20% — that could be a long way off. For now, caffeine might be your best bet for that purpose. What we are thinking about in the more immediate future is the possibility of using drugs to temporarily and dramatically change receptor movement. The goal here is neuroprotection after injury.”

    A Science of Connections
    As he talks about his research, it’s clear that Beattie places a high value on his collaborations with fellow researchers. His sentences roll out with neat little footnotes referencing this old colleague, that former advisor. “This may surprise some people,” he says, “but being a researcher is actually a very social job. It’s highly interactive and you need to communicate effectively to be productive.”

    That’s one reason he joined the Research Institute. “This is a close-knit community of researchers,” he says. “Not only can I share some of the big equipment and the laboratory space, I’m also looking forward to collaborations with my new colleagues here as well as with my old friends and colleagues at UCSF, Stanford, and the biotech companies around the Bay Area. It helps to be so close to all these strongholds.”

    The other special feature of research at California Pacific Medical Center, according to Dr. Beattie, was its pure focus on research. “My colleagues starting labs at universities talk about how many other things they need to do. It’s always a fight to protect your research time and here it’s what you’re paid to do. So now I’ve got this opportunity and I can jump right on it.”