Abstract
Accumulating evidence has suggested that prenatal exposure to methadone causes multiple adverse effects on human brain development. Methadone not only suppresses fetal neurobehavior and alters neural maturation, but also leads to long-term neurological impairment. Due to logistical and ethical issues of accessing human fetal tissue, the effect of methadone on brain development and its underlying mechanisms have not been investigated adequately and are therefore not fully understood. Here, we use human cortical organoids which resemble fetal brain development to examine the effect of methadone on neuronal function and maturation during early development. During development, cortical organoids that are exposed to clinically relevant concentrations of methadone exhibited suppressed maturation of neuronal function. For example, organoids developed from 12th week till 24th week have an about 7-fold increase in AP firing frequency, but only half and a third of this increase was found in organoids exposed to 1 and 10 μM methadone, respectively. We further demonstrated substantial increases in INa (4.5-fold) and IKD (10.8-fold), and continued shifts of Na+ channel activation and inactivation during normal organoid development. Methadone-induced suppression of neuronal function was attributed to the attenuated increase in the densities of INa and IKD and the reduced shift of Na+ channel gating properties. Since normal neuronal electrophysiology and ion channel function are critical for regulating brain development, we believe that the effect of prolonged methadone exposure contributes to the delayed maturation, development fetal brain and potentially for longer term neurologic deficits.
Highlights
Evidence has shown that methadone-exposed fetuses displayed neurobehavioral suppression such as declined motor activity and movement duration, as well as decreased coupling between fetal movement and fetal heart rate in utero (Wouldes et al, 2004; Jansson et al, 2005, 2011)
Human cortical organoids were generated from induced pluripotent stem cells (iPSCs) lines as described in our recent work (Nageshappa et al, 2016; Trujillo et al, 2019; Yao et al, 2020)
These results demonstrate that specific types of cells at the edge of cortical organoids can be identified by combining patch-clamp recordings and immunocytochemistry
Summary
Evidence has shown that methadone-exposed fetuses displayed neurobehavioral suppression such as declined motor activity and movement duration, as well as decreased coupling between fetal movement and fetal heart rate in utero (Wouldes et al, 2004; Jansson et al, 2005, 2011). Various investigations showed that children with prenatal methadone exposure have abnormal intellectual capacities and neurobehavioral changes such as lower attention span, higher fear, aggression and anxiety, indicating the existence of long-term neurological impairment caused by in utero methadone exposure (Strauss et al, 1976; Rosen and Johnson, 1982; Bauman and Levine, 1986; Davis and Templer, 1988; Bunikowski et al, 1998; Hunt et al, 2008) Some of these studies found that children exposed to methadone had impaired cognitive development and language ability (Rosen and Johnson, 1982; Davis and Templer, 1988; Hunt et al, 2008). Human brain organoids provide a great opportunity to investigate the neurodevelopmental effects of prenatal opioid exposure
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