Low Retinal Dehydrogenase 1 (RALDH1) Level in Prepubertal Boys with Autism Spectrum Disorder: A Possible Link to Dopamine Dysfunction?

Abstract

ObjectiveRetinal dehydrogenase 1 (RALDH1) is a cytosolic enzyme which acts both as a source of retinoic acid (RA) and as a detoxification enzyme. RALDH1 has key functions in the midbrain dopaminergic system, which influences motivation, cognition, and social behavior. Since dopamine has been increasingly linked to autism spectrum disorder (ASD), we asked whether RALDH1 could contribute to the autistic phenotype. Therefore, we investigated for the first time the levels of RALDH1 in autistic patients. To further assess the detoxification function of RALDH1, we also explored 4-hydroxynonenal protein adducts (4-HNE PAs) and reduced glutathione (GSH) levels. Moreover, considering the effect of testosterone on RALDH1 expression, we measured the second to fourth digit ratio (2D:4D ratio) for both hands, which reflects exposure to prenatal testosterone.MethodsMale patients with ASD (n=18; age, 62.9±4.3 months) and healthy controls (n=13; age, 78.1±4.9 months) were examined. Erythrocyte RALDH1, serum 4-HNE PAs and erythrocyte GSH levels were measured using colorimetric assays, and digit lengths were measured using digital calipers.ResultsWe found significantly lower (−42.9%) RALDH1 levels in autistic patients as compared to controls (p=0.032). However, there was no difference in 4-HNE PAs levels (p=0.368), GSH levels (p=0.586), or 2D:4D ratios (p=0.246 in the left hand, p=0.584 in the right hand) between healthy controls and autistic subjects.ConclusionWe concluded that a subset of autistic patients had a low RALDH1 level. These results suggest that low RALDH1 levels could contribute to the autistic phenotype by reflecting a dopaminergic dysfunction.

Reward-Related Behavioral, Neurochemical and Electrophysiological Changes in a Rat Model of Autism Based on Prenatal Exposure to Valproic Acid

“…Brain regions involved in the control of social behavior include corticolimbic structures and their altered functionality may represent one neural substrate contributing to the social impairments characteristic of ASD (Scott-Van Zeeland et al, 2010; Chevallier et al, 2012; Ameis and Catani, 2015; Supekar et al, 2018). Notably, these regions are subjected to modulation by dopaminergic neurons and it has been suggested that a dysfunction of dopaminergic neurotransmission in the mesocorticolimbic circuit leads to the social deficits observed in ASD (Pavăl et al, 2017): thus, it has been demonstrated that striatal MSNs show enriched expression of genes associated with ASD (Chang et al, 2015) and that ASD-associated mutations affect specific MSN subtypes (Portmann et al, 2014; Rothwell et al, 2014; for a review, see Rothwell, 2016).…”

Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder

“…Notably, the DS has been related to behavioral skills belonging to executive functioning, such as analyzing, planning and prioritizing (Seeman, 2010 ; Baronio et al, 2014 ). In line with that, children diagnosed with ASD were found to show deficits in tasks linked to executive functioning, including response/selection, planning/working memory and flexibility (Hellings et al, 2017 ; Paval et al, 2017 ). Moreover, the DS has strongly been linked to social behavior, attentional skills and perception, and motor activity, while development abnormalities in these areas have all been linked to ASD as well (Hellings et al, 2017 ; Paval et al, 2017 ).…”

“…This would completely exhibit new therapeutic tactic to the clinical control of ASD. Growing evidences suggest that a variety of several neurotransmitter systems such as ACh, 5-HT, DA, GABA, Glu, and HA are implicated in the onset and progression of ASD -along with genetic and environmental factors discussed below- (Shah and Wing, 2006 ; Bacchelli et al, 2015 ; Ellenbroek and Ghiabi, 2015 ; Wang et al, 2015 ; Chen et al, 2017 ; Hellings et al, 2017 ; Hellmer and Nystrom, 2017 ; Naaijen et al, 2017 ; Nakai et al, 2017 ; Paval, 2017 ; Paval et al, 2017 ; Figure 1 ).…”

“…ASD is strongly associated with a mutation in the DA transporter gene SLC6A3 , which codes for a protein that contributes to regulation of DA levels in the brain. In fact, DAT is the crucial regulator of DA homeostasis and alteration of this homeostasis as a consequence of DAT dysfunction is associated with ASD and other neuropsychiatric conditions (Hamilton et al, 2013 ; Hellings et al, 2017 ; Paval, 2017 ; Paval et al, 2017 ). Moreover, it has been found that the dopaminergic fibers arising from the ventral tegmental area (VTA) project to the prefrontal cortex (PFC) and to regions of the limbic system, such as the nucleus accumbens (NAcc), forming the mesocorticolimbic (MCL) circuit.…”

“…Moreover, it has been found that the dopaminergic fibers arising from the ventral tegmental area (VTA) project to the prefrontal cortex (PFC) and to regions of the limbic system, such as the nucleus accumbens (NAcc), forming the mesocorticolimbic (MCL) circuit. This circuit was found to be involved in high order brain functions, such as emotional social behavior, reward, motivation and cognition (Paval et al, 2017 ) (Hellings et al, 2017 ; Figure 1 ). Notably, the DS has been related to behavioral skills belonging to executive functioning, such as analyzing, planning and prioritizing (Seeman, 2010 ; Baronio et al, 2014 ).…”