The Effects of Prenatal Dexamethasone Exposure on Brain Metabolic Homeostasis in Adulthood: Implications for Depression

Abstract

Since depression produces a long-term negative impact on quality of life, understanding the pathophysiological changes implicated in this disorder is urgent. There is growing evidence that demonstrates a key role for dysfunctional energy metabolism in driving the onset of depression; thus, bioenergetic alterations should be extensively studied. Brain metabolism is known to be a glucocorticoid-sensitive process, but the long-lasting consequences in adulthood following high levels of glucocorticoids at the early stages of life are unclear. We examined a possible association between brain energetic changes induced by synthetic glucocorticoid-dexamethasone treatment in the prenatal period and depressive-like behavior. The results show a reduction in the oxidative phosphorylation process, Krebs cycle impairment, and a weakening of the connection between the Krebs cycle and glycolysis in the frontal cortex of animals receiving dexamethasone, which leads to ATP reduction. These changes appear to be mainly due to decreased expression of pyruvate dehydrogenase, impairment of lactate transport to neurons, and pyruvate to the mitochondria. Acute stress in adulthood only slightly modified the observed alterations in the frontal cortex, while in the case of the hippocampus, prenatal exposure to dexamethasone made this structure more sensitive to future adverse factors.

Mitochondria in depression: The dysfunction of mitochondrial energy metabolism and quality control systems

“…As glucose metabolism supplies more than 95% of ATP in the brain, this may strongly suggests the intriguing possibility that decreased ATP level caused by mitochondrial disorders is critically involved in neurological diseases, including depression. 20,21 In the past decade, evidence from some patients with major depressive disorder (MDD) exhibits decreased glucose metabolism level in some brain regions related to emotion regulation, such as bilateral insula, left lentiform nucleus putamen and extra-nuclear, right caudate and cingulate gyrus. 22 Similarly, several studies have shown that the beta-nucleoside triphosphate, which arises from beta-ATP, is much lower in the basal ganglia of MDD patients.…”

“…In addition, it has been shown that prenatal Dex exposure results in depression-like behavior, accompanied by mitochondrial dysfunction and the diminished production of ATP in the frontal cortices or hippocampus of the adult rodents, and that improvement of mitochondrial function in brain improves the depression-like behavior. 11,21,34 Some studies from human and animals suggest that the deficiency of ATP resulting from mitochondrial disorders contributes to the pathogenesis of depression. It is widely known that ATP is mainly produced by aerobic and anaerobic glycolysis.…”

“…As the abnormality of mitochondrial oxidative phosphorylation is closely associated with the pathogenesis of depression, 21 multiple pieces of evidence suggest that antidepressants may ameliorate depression‐like behavior by enhancing the activity of the mitochondrial respiratory chain and the ATP production. For instance, it was observed that chronic Tianeptine administration up‐regulates the expression of mitochondrial energy metabolism‐related enzymes, such as Atp5b, Atp5o and Cytc, in hippocampal synaptosomal fractions of rats exposed to chronic social isolation 93 .…”

“…Of note, mitochondria are particularly important for brain because of both its high levels of energy use and inability to store large amounts of energy reserves in the form of glycogen. As glucose metabolism supplies more than 95% of ATP in the brain, this may strongly suggests the intriguing possibility that decreased ATP level caused by mitochondrial disorders is critically involved in neurological diseases, including depression 20,21 …”

“…demonstrated that acetyl‐L‐carnitine supplementation can improve mitochondrial function and promote ATP production, thereby ameliorating depression caused by intergenerational trauma. In addition, it has been shown that prenatal Dex exposure results in depression‐like behavior, accompanied by mitochondrial dysfunction and the diminished production of ATP in the frontal cortices or hippocampus of the adult rodents, and that improvement of mitochondrial function in brain improves the depression‐like behavior 11,21,34 …”