Abstract
Dopamine signaling has numerous roles during brain development. In addition, alterations in dopamine signaling may be also involved in the pathophysiology of psychiatric disorders. Neurodevelopment is modulated in multiple steps by reactive oxygen species (ROS), byproducts of oxidative metabolism that are signaling factors involved in proliferation, differentiation, and migration. Hexokinase (HK), when associated with the mitochondria (mt-HK), is a potent modulator of the generation of mitochondrial ROS in the brain. In the present study, we investigated whether dopamine could affect both the activity and redox function of mt-HK in human neural progenitor cells (NPCs). We found that dopamine signaling via D1R decreases mt-HK activity and impairs ROS modulation, which is followed by an expressive release of H2O2 and impairment in calcium handling by the mitochondria. Nevertheless, mitochondrial respiration is not affected, suggesting specificity for dopamine on mt-HK function. In neural stem cells (NSCs) derived from induced-pluripotent stem cells (iPSCs) of schizophrenia patients, mt-HK is unable to decrease mitochondrial ROS, in contrast with NSCs derived from healthy individuals. Our data point to mitochondrial hexokinase as a novel target of dopaminergic signaling, as well as a redox modulator in human neural progenitor cells, which may be relevant to the pathophysiology of neurodevelopmental disorders such as schizophrenia.
Highlights
Dopamine (DA) is an important neurotransmitter in multiple areas of the adult brain
Similar to the results obtained in mature neurons [25], activation of mitochondria-bound hexokinase (mt-HK) in control neural progenitor cells (NPCs) by 2-DOG prevented the generation of reactive oxygen species (ROS) by mitochondria because significantly lower levels of ROS were detected in the intracellular and extracellular media (Figure 2A,B)
High-resolution respirometry of control and dopamine-treated NPCs was used to determine whether this effect is μM for 48 h). (B) Representative measurement of H2O2 release rate assessed fluorimetrically by Amplex Red-Peroxidase system, specific for H2O2, in intact NPCs. (C) Quantification of the rate of H2O2 release upon dopamine treatment when compared to control
Summary
Dopamine (DA) is an important neurotransmitter in multiple areas of the adult brain. Dopamine has been studied from a neurodevelopmental perspective because DA receptors are expressed very early in the development of the central nervous system before synaptogenesis [2,3]. Dopaminergic signaling is known to modulate crucial processes, such as the regulation of gene expression, proliferation, and differentiation [4]. Altered dopamine signaling during ontogenesis may be involved in the aetiology of neuropsychiatric disorders [5]. Expression of elevated levels of D2 dopaminergic receptors during development in transgenic mice alters dopamine signaling that leads to abnormal behavior and impaired working memory even when receptor density is normalized in the adult animals [6]. A transient increase in dopaminergic signaling during a critical window in neurodevelopment of License 4.0 (CC BY)
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