How Can the Glutamate and GABA Systems Become Dysregulated in Depression?

Glutamate and GABA work together to help keep the brain’s activity in balance.

Glutamate is the brain’s main “go” signal. It helps nerve cells become active and communicate.

GABA is the brain’s main “slow down” signal. It helps calm activity and prevents brain circuits from becoming overactive.

A healthy brain needs the right balance between the two.

In the Prefrontal Cortex

The prefrontal cortex helps with:

• Concentration
• Planning
• Emotional control
• Decision-making
• Managing stress With long-term stress, glutamate activity can become too strong while GABA’s calming effect may become weaker.

This can make brain communication less stable and may contribute to: poor concentration, mental fatigue, negative thinking and difficulty regulating emotions.

In the Amygdala

The amygdala helps the brain respond to threat and stress.

If there is too much excitatory glutamate activity and not enough calming GABA activity, the amygdala may become overly reactive.

This may contribute to anxiety, irritability, emotional sensitivity, hypervigilance and feeling constantly on edge.

In the Hippocampus

The hippocampus is important for memory, learning and stress regulation.

Long-term stress and excessive glutamate activity can interfere with healthy communication between brain cells and reduce the brain’s ability to adapt and form strong connections.

This may contribute to memory difficulties, persistent negative thinking and greater sensitivity to stress.

Why Do Glutamate and GABA Become Dysregulated?

There is usually no single cause.

Factors such as: chronic stress, genetics, inflammation, poor sleep and changes in other brain chemicals

can disturb the balance between excitation and calming activity.

A simple example is:

1. Long-term stress
2. Brain circuits stay highly activated
3. Glutamate activity may become excessive
4. GABA may not provide enough calming control
5. Brain communication becomes less balanced
6. Mood, anxiety and thinking may be affected

A Simple Way to Think About It

Think of: Glutamate as the accelerator and: GABA as the brake.

The brain needs both.

If the accelerator is pushed too hard or the brake is too weak, some brain circuits may become overactive and less able to function normally.

This can show up as:

• Anxiety
• Feeling overwhelmed
• Irritability
• Poor concentration
• Sleep problems
• Mental fatigue
• Difficulty coping with stress That is why it is more accurate to think of depression as involving glutamate and GABA dysregulation, rather than simply having “too much glutamate” or “too little GABA.”