Internal medicine

Neuroscience

Receptor

Electrophysiology

Central nervous system

Premovement neuronal activity

Biology

Cortical spreading depression

Bursting

Astrocyte

Migraine

Neuron

Optogenetics

Biochemistry

Glutamate receptor

Medicine

Nature

Increased expression of the potassium channel Kir4.1 on astrocytes in the lateral habenula drives neuronal bursting in rodent models of depression. The lateral habenula (LHb) is a region of the brain that is associated with aversion and other negative emotions. Hailan Hu and colleagues present a pair of papers in this week's issue on the role of burst firing in LHb neurons in depression in rats. First, they show that ketamine, a drug that can be used as an antidepressant, blocks LHb neuron bursting activity, and that both NMDAR and low-voltage-sensitive T-type calcium channels (T-VSCCs) are required for the drug to be effective. In the second study, the authors identify a potential mechanism for regulating this bursting behaviour that could represent a new therapeutic target. Levels of an astroglial potassium channel, Kir4.1, covary with the degree of membrane hyperpolarization and bursting activity of LHb neurons, as well as depression-related behaviours in various rodent models. The team suggest that blocking LHb neuron bursting activity could revive reward centres in the brain and elevate mood, and provide a model framework for developing rapid-acting antidepressants. Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia–neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression.

Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression