GABAergic Interneuron-Astrocyte Interaction Facilitates Complex Behaviours

Post by D. Chloe Chung

What's the science?

Interneurons that release a type of inhibitory neurotransmitter called GABA regulate complex behaviours such as decision-making. Along with other neurotransmitters, GABA released at synapses can be detected by astrocytes that express receptors for GABA (GABABRs). Until now, it has not been well understood whether interaction between GABAergic interneurons and astrocytes can impact complex behaviours. This week in Nature Neuroscience, Mederos and colleagues found that GABAergic signaling to astrocytes plays an important role in modulating behavioural outcomes, by applying electrophysiology and optogenetics to a novel mouse model.

How did they do it?

To test the functional role of astrocytes sensing GABA, the authors made a new mouse model that is designed to lack astrocytic GABABRs in the medial prefrontal cortex (mPFC), a brain area that controls decision-making. These mice, along with the control mice, underwent a behavioural test that measures working memory and decision-making. Specifically, mice were made to choose which arm of the simple maze (T-maze) to enter based on their spatial memory (i.e. which arm they previously took food from). During the behavioural test, the authors monitored dynamic changes in neural activity in the mouse brain using electrophysiological techniques. In parallel, the authors used a slice of mouse mPFC to perform ex vivo recordings of neuronal firing while mimicking interneuron-astrocyte signaling. To understand direct consequences of mPFC astrocyte activation on mouse behaviors, the authors injected virus into the brains of both control mice and genetically modified mice to specifically stimulate astrocytes using melanopsin, a light-sensitive G-protein.

What did they find?

The authors first observed that mice without GABABRs in the mPFC astrocytes had impaired working memory and decision-making compared to control mice, as shown by the T-maze test. From simultaneous electrophysiological recordings, the authors found that low gamma oscillations (30–60 Hz) in the brain were substantially reduced while mice were experiencing impaired decision-making. These findings collectively indicate that deficits in GABAergic astrocyte signaling disrupted brainwaves and neuronal firing properties that are critical for decision-making, subsequently impairing behavioural outcomes. Ex vivo mPFC recording further revealed that interaction between GABAergic interneurons and astrocytes through GABABRs importantly regulates the inhibitory neural circuitry. Interestingly, when the authors optogenetically activated mPFC astrocytes, control mice performed better at the decision-making test. The observed improvement in decision-making was accompanied by enhanced neuronal firing and gamma oscillations, suggesting that activation of astrocytes in the mPFC can markedly improve cognitive capacity. Based on this finding, the authors performed a similar optogenetics experiment with mice that lack GABABRs in mPFC astrocytes and found that optogenetic stimulation of mPFC astrocytes rescued behavioural deficits. In other words, mice that were once impaired in their decision-making due to the loss of GABAergic astrocyte signaling behaved similarly to naïve mice upon selective activation of astrocytes.

What’s the impact?

This study is the first to demonstrate that GABAergic signaling involving interneurons and astrocytes in the mPFC is critical in modulating decision-making. Past studies have reported that behaviour can be impacted by astrocytes in brain regions other than mPFC such as the hippocampus and amygdala. This work expands the functional role of astrocytes, presenting them as essential players in facilitating complex behaviour controlled by mPFC. As the authors suggested, given the variety of interneurons in the brain, it will be interesting to further investigate whether other types of interneurons can also interact with astrocytes in a similar manner.

Mederos et al. GABAergic signaling to astrocytes in the prefrontal cortex sustains goal-directed behaviors. Nature Neuroscience (2020). Access the original scientific publication here.