The role of melatonin in the neurodevelopmental etiology of schizophrenia: A study in human olfactory neuronal precursors

Abstract

Dim light exposure of the mother during pregnancy has been proposed as one of the environmental factors that affect the fetal brain development in schizophrenia. Melatonin circulating levels are regulated by the environmental light/dark cycle. This hormone stimulates neuronal differentiation in the adult brain. However, little is known about its role in the fetal human brain development. Olfactory neuronal precursors (ONPs) are useful for studying the physiopathology of neuropsychiatric diseases because they mimic all the stages of neurodevelopment in culture. Here, we first characterized whether melatonin stimulates neuronal differentiation in cloned ONPs obtained from a healthy control subject (HCS). Then, melatonin effects were evaluated in primary cultures of ONPs derived from a patient diagnosed with schizophrenia (SZ) and an age- and gender-matched HCS. Axonal formation was evidenced morphologically by tau immunostaining and by GSK3β phosphorylated state. Potassium-evoked secretion was assessed as a functional feature of differentiated neurons. As well, we report the expression of MT1/2 receptors in human ONPs for the first time. Melatonin stimulated axonal formation and ramification in cloned ONPs through a receptor-mediated mechanism and enhanced the amount and velocity of axonal and somatic secretion. SZ ONPs displayed reduced axogenesis associated with lower levels of pGSK3β and less expression of melatonergic receptors regarding the HCS ONPs. Melatonin counteracted this reduction in SZ cells. Altogether, our results show that melatonin signaling is crucial for functional differentiation of human ONPs, strongly suggesting that a deficit of this indoleamine may lead to an impaired neurodevelopment which has been associated with the etiology of schizophrenia.

Chronobiology Revisited in Psychiatric Disorders: From a Translational Perspective

“…Galván-Arrieta et al reported a reduction in axogenesis associated with lower levels of phosphorylated GSK-3 subtype β and less expression of melatonergic receptors in patients with schizophrenia compared with healthy controls. These findings may indicate a melatoninderived neurodevelopmental deficit at a cellular level (Galván-Arrieta et al, 2017). The absence of melatonin rhythmicity, decreased nocturnal secretion of melatonin, and phase advance in melatonin circadian rhythms have also been described in patients with schizophrenia (Rao et al, 1994;Anderson and Maes, 2012;Yates, 2016).…”

The Timing of Melatonin Administration Is Crucial for Its Antidepressant-Like Effect in Mice

“…One possible explanation could be that a lasting period of hours is necessary to observe the behavioral response, since it is known that the antidepressant behavior is related to brain plastic changes that take hours to be established (for a review see Valdés-Tovar et al, 2018) [48]. For instance, dendritic and axonal formation as well as synaptogenesis was reported to take place after 6 h of melatonin administration [13,25]. However, the changes observed under acute administration at ZT18 and tested 30 min later in the TST are also probably the result of electrophysiological fast responses as reported to be elicited by melatonin [30,49].…”

“…Additionally, this indolamine prompts neurodevelopment, is an anti-apoptotic molecule and modulates neuroinflammation among other actions [13,14,15,16,17]. The hippocampus, the brain region which integrates spatial memory, learning and cognition [18,19], is also one of the main structures affected in patients with major depression, showing atrophy and a decreased volume size by brain imaging studies [20].…”

Pleiotropic Effects of Melatonin

“…A recent study showed that signaling through melatonin was very important for the functional differentiation of human ONPs indicating that melatonin deficiency or deficient melatonin signalling could result in impaired neurodevelopment resulting in psychosis. [96] The second most common neurodegenerative disorder reported is the PD after AD. It is characterized by a progressive loss of dopamine in the substantia nigra and striatum.…”