Ketamine Blocks Burst Firing to Provide Depression Relief

What's the science?

Ketamine is a drug that binds to and blocks NMDA receptors found on neurons. It provides fast acting and sustained relief of depression symptoms, however, the mechanisms underlying ketamine’s effectiveness are unknown. A brain region called the lateral habenula, involved in reward processing and negative emotions, is known to have abnormal “burst” activity in patients with depression. This week in Nature, Yang and colleagues determine whether abnormal activity in the lateral habenula can drive depression-like behaviours, and how this might be reversed by ketamine.

How did they do it?

They tested to see if ketamine infusion into the lateral habenula relieved depression symptoms (improved mobility in the forced swim test) in learned helpless (depressed) rats. Next, they performed whole-cell patch-clamp (a method used to measure the electrical currents in a neuron) on lateral habenula neurons to determine : 1) whether the spontaneous neuronal activity in these cells is abnormal in depressed rats, 2) whether these abnormalities could be reversed by NMDA blockers and, 3) if changing the resting state membrane potential of the cell can alter the pattern of spiking activity in the lateral habenula. They then used optogenetic techniques to mimic the bursting activity seen in the lateral habenula of depressed mice to determine whether this activity was sufficient to induce depression behaviours.

What did they find?

Ketamine administered in the lateral habenula alleviated the depression symptoms in rats. Increased burst firing occurred in neurons in the lateral habenula of depressed rats. These burst patterns were completely blocked by ketamine, but not by other typically used antidepressant drugs. The bursting properties of the lateral habenula could be altered by changing the membrane potential of the cell, suggesting a new potential therapeutic target, the T-type calcium channel. They were also able to induce depression-like symptoms in rats by using optogenetics to control the pattern of burst firing in the lateral habenula.

What's the impact?

This is the first study to describe the mechanisms by which ketamine has fast acting depression relief. We now know that burst firing underlies depressive symptoms in rats, and that this can be blocked with ketamine. Understanding how and where ketamine acts in the brain is an important step towards developing new therapies for depression.  

Yang et al., Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. (2018). Access the original scientific publication here.

Rachel Bosma, PhD contributed to this BrainPost