Astrocyte glutamate metabolism regulates depressive behavior induced by long-term high-fat diets

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Depression coexists
with many chronic diseases, metabolic disorders, and cardiovascular diseases.
Some antidepressants have been shown to improve blood sugar levels in people with depression and type 2 diabetes comorbidities, while some antidiabetic drugs may alleviate depressive symptoms
.

Disorders of the dopaminergic neural circuit of the midbrain, consisting of dopaminergic (DA) neurons in the ventral covered region and GABAergic neurons in the nucleus accumbens (NAc), are important pathophysiological mechanisms of
depression.

On September 30, 2022, Yu-Min Kuo's team at National Cheng Kung University in Taiwan revealed that long-term high-fat diets overactivate ventral hippocampal glutamate synaptic transmission through glutamate transporters of astrocytes, causing depressive behavior
.
After 12 weeks of high-fat diet, mice experienced depressive behaviors such as sugar water deficiency and increased immobility time in forced swimming experiments
.
In addition, there was an increase in glutamate release in the NAc region, but there was no change in the expression of glutamine synthase and glutamate transporter in this region, suggesting that the increase in glutamate in this region may be due to overactivated glutamergic input
.

Figure 1: Long-term high-fat diet causes depressive behavior

Retrograde tracer virus injected into the NAc region was found in areas such as the medial prefrontal cortex (mPFC), the basil-lateral amygdala (BLA), and the ventral hippocampus (vHPC
).
Immunofluorescence experiments found that the high-fat diet mainly activates neurons in the vHPC region, and the mPFC and BLA regions have less
neuronal activation.
Chemical genetics Chronic inhibition of vHPC → NAc loops can significantly inhibit the increase
in immobility time caused by high-fat diets.
This suggests that overactivation of the NAc loop → vHPC mediates depressive behavioral disorders caused by high-fat diets
.

Levels of glutamate transporters GLAST and GLT-1 proteins in the vHPC region decreased after a high-fat diet, while inhibitory synaptic transporters did not change
.
In addition, there was no change
in GLAST and GLT-1 protein levels in the mPFC and BLA regions.

Figure 2: A high-fat diet causes overactivation of glutamate in the vHPC → NAc loop

GLAST and GLT-1 are responsible for the clearance of almost all glutamic acid in the synaptic space, and these two proteins are mainly expressed
on astrocytes.
Simultaneous reduction of the GLAST and GLT-1 proteins in the vHP region by viral strategy specificity causes depressive behavior
in mice.
Specific elevations in GLAST and GLT-1 proteins significantly alleviate depressive behavior caused by high-fat diets
.

Riluzole is a glutamate excitatory toxic antagonist that is currently approved by the US FDA for the treatment of amyotrophic lateral sclerosis
.
Intraperitoneal injection or vHP injection of Riluzole in the brain region can significantly increase GLAST and GLT-1 protein levels, inhibit glutamate glutamate input overactivation caused by high-fat diets, and significantly improve depressive behavior
.

In this review, it was found that long-term high-fat diets reduced expression of gliacy-derived glutamate transporters GLAST and GLT-1 in the hippocampus, and glutamate clearance was reduced, causing over-activation of glutamate input into the vHPC → NAc loop, leading to depressive behavior
.

【References】

1.
https://doi.
org/10.
1038/s41380-022-01787-1

The images in the article are from references