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When we think about how the brain works—or how to fix it—we tend to think of neurotransmitters such as serotonin or dopamine. But the brain is an electric organ, its currency the impulses that fly across thousands of miles of neurons. As I describe in my new book, The Memory Thief and the Secrets Behind How We Remember: A Medical Mystery, more electrical activity is not always better. In fact, hyperactivity in the hippocampus—the brain’s memory center—is an early sign of Alzheimer’s disease that is gaining overdue interest as a therapeutic target.
Neurons come in two main “flavors,” excitatory and inhibitory. When an excitatory neuron receives enough input from other excitatory neurons, it fires, passing that signal along its axon to partners downstream. Inhibitory neurons usually tell other neurons not to fire. They are less plentiful than excitatory neurons but more diverse. In some ways, they are the real brains of the system, the machines in the background that pace and coordinate a ceaseless hum of electrical activity.
The best-studied inhibitory neuron is called a basket cell, so named because its axon splits into many filaments and wraps like a basket around the cell body of other neurons, the point where it can exert maximum control. Basket cells have a relatively simple job: they act as gatekeepers, allowing excitatory neurons to fire or preventing them from doing so. A single basket cell can control and synchronize the output of hundreds or even thousands of excitatory neurons, switching them on and off with precise timing and setting up a rhythmic tug-of-war that creates brain waves. Brain waves, in turn, allow information to be coordinated and transmitted across long distances. When inhibitory neurons stop working well, this delicate balance between excitation and inhibition degrades, and brain waves become less coherent.
When researchers first identified hippocampal hyperactivity as an early Alzheimer’s symptom, they assumed it was compensatory, a way to turn up the volume on weak communication between neurons. Researchers now understand that this loss of inhibition is like background static that interferes with memory retrieval, and clues point to inhibitory neurons as essential players in the chain of events that occurs as Alzheimer’s progresses. For example, even cognitively normal older adults have hyperactivity in the hippocampus and accumulation of tau protein along with it. In addition to sticky amyloid beta plaques, these toxic tau proteins are a defining feature of the disease. Another clue is that seizures, which occur when excitatory neurons fire uncontrollably, are more common in people with Alzheimer’s than without, are thought to accelerate its progression, and may appear in the early stages—perhaps even before other signs of disease. A third clue is that one type of brain wave, called gamma, is weaker in people with Alzheimer’s. These insights suggest that adjusting the balance between excitation and inhibition could improve memory and slow down the disease’s progression.
Researchers are investigating several approaches to recalibrating that balance. The furthest along is a Phase 3 clinical trial of a widely used anti-seizure drug called levetiracetam. The US company behind the trial, AgeneBio, is testing whether an extended-release, very low dose reduces background hyperactivity enough to improve memory in the earliest stages of Alzheimer’s. A second angle of attack is to manipulate the brain waves generated by inhibitory neurons. Researchers at a company called Cognito Therapeutics, at MIT, and elsewhere are running several independent trials that use external flickering lights and audio to entrain and strengthen gamma rhythms. A third tack, currently being tested in mice, is to transplant genetically enhanced inhibitory neurons into the brain.
Faulty electrical communication is also thought to play a role in other brain disorders and diseases, including epilepsy, schizophrenia, depression, and autism. Our understanding of inhibitory neurons is in its infancy compared to what we know about neurotransmitters. Because neurotransmitters play multiple roles and therefore have many side effects, they can act like a pharmacological blanket laid down over the whole brain’s delicate workings. Perhaps, if researchers figure out how to target the inhibitory neurons involved in each illness, they could develop more sophisticated ways of helping hundreds of millions of people around the world who suffer from these debilitating brain diseases.
Lauren Aguirre is a science journalist whose work has appeared in the PBS series NOVA, The Atlantic, Undark Magazine, and STAT. Read an excerpt from The Memory Thief here.
