Time for a Brake

Our brains, like race car drivers straining for the starting signal, are generally raring to go. Given a trigger, our neurons spring into action, relaying information to their neighbors. And like those drivers, we’d quickly run into trouble without a sturdy brake. That’s the role of GABA, or gamma-aminobutyric acid: It keeps neurons from firing after their mission is accomplished.

GABA, chemically distinct from such neurotransmitters as serotonin and dopamine, has only one chemical peer in the brain—glutamate. The two are widely distributed and work together like a gas pedal and brake to regulate neuronal activity. The gas pedal glutamate binds to neuronal receptors, stimulating the cells to fire. Their work done, GABA takes over, dampening excitability.

When functioning properly, the system helps regulate brain cell activity. But new research suggests that GABA, especially through its balancing act with glutamate, plays a significant role in disorders from depression and anxiety to schizophrenia and autism.

In the journal Biological Psychiatry, Penn State University biologist Bernhard Lűscher reports that depression may arise from a deficit in GABA, throwing GABA and glutamate out of balance. In an attempt to compensate, the body increases production of glutamate. At first, the glutamate surge leads to lots of neuron excitation. But eventually the receptors for glutamate retreat, preventing brain cells from firing.

The result: feelings of numbness and disengagement from the world. “You’re blunted,” says Lűscher. “You can’t be stimulated to have fun or get excited.” Since stress is known to impair GABA transmission, the research adds to the mounting evidence that stress plays a major role in depression. GABA deficits or dysfunction at any time in life may bring on depression and its common accomplice, anxiety, scientists believe.

But GABA dysfunction early in life may set the stage for schizophrenia and autism. At a critical prenatal period of development, GABA inhibition may create the hearing and motor skill problems linked to autism spectrum disorder or the emotional imbalance and diminished cognitive function of schizophrenia. Both experimental and clinical data suggest that the GABA balancing system may be particularly vulnerable to disruption by genetic and environmental forces.

The neurotransmitter behaves very differently during fetal development than after birth. Prenatally, instead of stopping neurons from firing, GABA triggers them. After birth, glutamate takes over, and GABA reverses course, becoming a neuron inhibitor. The developmental complexity, unfortunately, creates opportunities for the GABA system to go awry.

The new insight into GABA’s role in depression suggests a new approach to treatment, and Lűscher and his colleagues have found that a single small dose of the anesthetic ketamine can provide short-term relief of depression. The ketamine stimulates glutamate receptors and GABA function, restoring the balance between GABA and glutamate. It acts in hours—significantly faster than most other antidepressants—to energize patients. “People wake up and say, ‘Let’s do stuff,’ after being unresponsive for years,” Lűscher reports. The effects last a few days to one week.

Lűscher plans to explore genetically enhancing GABA transmission as a novel depression treatment. He is also investigating the relationship of GABA to conditions such as obesity. “We know that our diet can affect how we feel, and people who are overweight are more vulnerable to depression,” he says. “That suggests that metabolism and mood disorders have something in common.”

GABA is widely available as a dietary supplement. However, there is no firm evidence that, taken by mouth, the substance crosses the blood-brain barrier to have any effect on nervous system function.

GABA Gone Wrong

GABA deficit is linked to:

• Anxiety
• Depression
• Autism spectrum disorder
• Schizophrenia
• Bipolar disorder
• Epilepsy

GOT GABA?

• Along with its partner, glutamate, GABA is the most widespread neurotransmitter in the brain.
• Before birth, GABA stimulates the action of brain cells; after birth, the neurotransmitter reverses course to stop neurons from firing.
• Ketamine, experimentally used to treat depression, may help by restoring balance to the GABA-glutamate system.
• Bacteria in the gut synthesize GABA.
• The brain is not the only site of GABA activity; GABA regulates physiologic functions in the gastrointestinal tract as well.
• Scientists believe that GABA may play a role in regulating muscle tone throughout the human body.
• In insects, GABA helps to activate muscles.
• Some plants, including tomatoes, contain GABA, which helps them resist environmental stress.