Nature Communications: Hippocampal astrocytes regulate anxious behavior

Astrocytes play a key role in regulating synaptic transmission in neurons: the branch structure of astrocytes distributed around neurons senses ongoing changes in synaptic signals through neurotransmitter receptors and influences synaptic transmission
by releasing neurotransmitters.
Reducing vesicle release by hippocampal astrocytes inhibits the formation of cognitive memory, and chronic activation of astrocytes enhances fear memory
.

Post-traumatic stress disorder and depression present with abnormal, uncontrolled anxiety states in which astrocytes are involved
.
The number and density of astrocytes in the hippocampus and prefrontal cortex of the brain decreases
after autopsy in patients with depression.
In addition, in animal models, riluzole or fluoxetine antipsychotics can attenuate stress-induced decrease
in the number of astrocytes.

On November 7, 2022, Sung Joong Lee's research team at Seoul National University in South Korea revealed that hippocampal astrocytes regulate anxiety through ATP-mediated synaptic homeostasis
.

By simulating the elevated cross maze experiment with virtual reality technology, mice prefer to stay in the closed arm area
.
Two-photon microscopy in vivo imaging techniques imaged head-fixed mice and observed an increase
in intracellular calcium ion activity in most hippocampal astrocytes as mice entered the virtual open-arm region.
After further optogenetic specific activation of hippocampal astrocytes, the time for mice to enter the open arm region increased, and the entry of mice into the central region was also promoted in open field experiments, which indicated that activation of hippocampal astrocytes had anxiolytic effects
.

Figure 1: VR technology combined with two-photon microscopy to dynamically monitor astrocytes activity

Immunofluorescence experiments showed that neuronal activity in the surrounding area after photoactivation of hippocampal astrocytes was also significantly increased, and electrophysiological experiments showed that activation of hippocampal astrocytes could enhance spontaneous postsynaptic current
.

Figure 2: Photoactivation of hippocampal astrocytes anxiolytic

Activated astrocytes release neurotransmitters
such as ATP, glutamate and D-serine.
However, the researchers found through ex vivo experiments that activating astrocytes promoted the release of ATP, but the release of glutamate and D-serine did not increase
.
Electrophysiological experiments further showed that ATP can enhance spontaneous excitatory postsynaptic current
in hippocampal neurons.
Purinegic receptor antagonists block the increase in spontaneous excitatory postsynaptic current in neurons caused by photoactivation of astrocytes, suggesting that the ATP receptor signaling pathway is involved in the process
by which astrocytes enhance neuronal activity.

Photoactivation of hippocampal astrocyte cells after administration of purinegic receptor antagonists did not increase the residence time of mice in the open arm region of the elevated cross maze, nor did it promote the residence time of mice in the central region of the open field experiment, indicating that activating hippocampal astrocyte activity after inhibiting the ATP signaling pathway could not exert anxiolytic effects
.

Figure 3: Blocking ATP signaling inhibits anxiolytic effects in hippocampal astrocytes

By finding that hippocampal astrocytes respond to the anxious environment by increasing intracellular calcium signaling, this regulatory effect is dependent on ATP, and intervention in hippocampal astrocytes activity may become a strategy for the treatment of
anxiety.

Original source:

Cho， WH.
， Noh， K.
， Lee， B.
H.
et al.
Hippocampal astrocytes modulate anxiety-like behavior.
Nat Commun 13， 6536 (2022).
https：//doi.
org/10.
1038/s41467-022-34201-z.