Origin of the astrocytes inducing depressive-like behaviors

We published a paper on origin of the astrocytes in the habenula modulating depressive-like behaviors in journal GLIA.

Aizawa H, Matsumata M, Oishi LAN, Nishimura F, Kasaragod DK, Yao X, Tan W, Aida T, Tanaka K. Potassium Release From the Habenular Astrocytes Induces Depressive-Like Behaviors in Mice. Glia. 2024 Nov 29. doi: 10.1002/glia.24647. Epub ahead of print. PMID: 39612187. [Link]

Habenula is an area modulating central monoamines level in the brain and implicated in depression. Indeed, imaging study frequently reported that patients with depression exhibited alterations in responsiveness of this region to the aversive and painful stimuli. Animal study also supported that view by showing anti-depressant effect of habenula lesion.

Habenula consists of neurons and glia as in the other brain regions. Astrocyte is one of the most abundant glial cell types in the brain and play significant roles in regulation of neuronal excitability. Our group has been showing that dysfunctional astrocytes in the habenula led to the depressive-like phenotypes in behaviors and sleep. Since the neuro-developmental defects are proposed in psychiatric disorders such as depression, it would be of primary importance to address the origin and function of these neurons and astrocytes.

Current study revealed that neurons and astrocytes in the habenula were primarily derived from the zone next to the ventricle of the developing brain expressing transcription factor Dbx1. Transgenic mice labeling the cells originated from that area gave rise to neurons and astrocytes before and after birth, respectively. In particular, cells born immediately after birth (0 to 3 days after birth) migrate radially toward the pial side and started to exhibit star-like shape for astrocyte.

By expressing functional probe ChR2 in those cells for activation of those cells by blue light, we examined the interplay between astrocytes and neurons in the habenula. Interestingly, activation of Dbx1-derived astrocytes elicited an increase of the neuronal firing. This seems to be mediated by potassium ion released from the astrocytes through inward rectifier-type potassium channel expressed in the astrocytes. Potassium ion released by those cells acted on and depolarized neurons to make it fire subsequently.

These interplay between neurons and astrocyte turned out to make the mice depressive-like. Such manipulation of astrocytes resulted in reduced locomotor activity, increased despair-like and anhedonia-like behaviors.

Collectively, we found that a small brain area was the source of neurons and astrocytes in the habenula whose interaction elicited depressive-like behaviors in mice. Since the origin of those cells were limited, developmental defects during such a small time window can affect their growth and neural circuit, which might induce depression. It also implicate a possibility that astrocyte and its release of potassium ion could be an interesting target to develop a novel anti-depressants in the future.