To explain the parallel effect
To explain the parallel effect of Dyrk1a on the glutamate transporter and fate of neural progenitors, the authors refer to previous reports showing that lengthening G1 by decreasing the activity of cyclin D1 induces the premature generation of neurons and depletion of the stem cell pool (). This is indeed consistent with observations by Najas et al. at mid/late-corticogenesis. Yet it is puzzling that more IPs and less neurons were also observed during early corticogenesis, which is the opposite of what one would expect from a manipulation that lengthens G1 (). The authors propose that this might be explained by intrinsic differences in progenitor cells and/or environmental cues present at early versus late stages of corticogenesis. Yet, this does not entirely solve the issue since reports have shown that lengthening G1 results in a transient increase in neurons both at the onset () as well as at mid-neurogenesis (). Perhaps, instead of differences in progenitors and/or cues within the niche, this discrepancy might be explained by the fact that previous studies were performed acutely and, often, tissue-specifically. While Najas et al. obtained an exquisite control of gene dosage, their manipulations were neither temporally nor spatially controlled among tissues physiologically expressing Dyrk1a.
Nevertheless, the powerful animal models generated and characterized by Najas et al. will be extremely useful in future research. They open up a number of possibilities, not only to study the pathology of DS during development, but also to investigate the role of Dyrk1a in the neurophysiology of postnatal neurons as these are known to display reduced synaptic activity and abnormal gene expression (), highlighting the pleiotropic effects of this complex disease.
Funding Support The authors were supported by the CRTD, the TUD and the DFG Collaborative Research CenterSFB655 (subprojects A20).
Dysfunction in dopaminergic signaling may be an underlying cause of different neuropsychiatric disorders, including schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder (ADHD), and autism (). The dopamine (DA) transporter (DAT) plays a critical role in regulating the strength of dopaminergic tone by clearing extracellular DA (). Interestingly, DAT is the site of action for psychostimulants such as amphetamine (AMPH), which is thought to elevate extracellular DA levels by competitively inhibiting DA uptake, ultimately causing reverse transport of DA (DA efflux) (). Growing evidence indicates a genetic link between DAT and autism (). The work by in this issue of has studied the functional consequences of a nonsynonymous genetic variant in the human DAT gene (SLC6A3) which converts Arg51 to tryptophan (SLC6A3 R51W) in a family with autism. Moreover, the authors showed that another autism-causing rare variant in the syntaxin 1A gene (STX1A), which converts Arg26 to glutamine (STX1A R26Q), disrupts the molecular mechanisms of reverse transport of DA. Based on these results, they concluded that rare variants causing a significant inhibition of reverse transport of DA may play a pathogenic role in autism. While it has been known for many years that reverse transport of DA may be involved in the maintenance of an optimal range of DA levels (), its exact role in the pathogenesis of neuropsychiatric disorders remains to be determined. The molecular analyses provided in the paper by elegantly demonstrate that alterations in reverse transport of DA may be involved in the pathogenesis of autism symptoms at least in the specific pedigrees. However, the question as to whether such rare genetic variants affecting the reverse transport of DA might influence the risk of common, sporadic forms of autism remains open. It is now widely accepted that rare genetic variants could play an important role in susceptibility to common diseases. In light of Cartier et al.\'s results, major resequencing efforts of the SLC6A3 and STX1A genes should be undertaken in large cohorts of individuals with autism, with significant insights into disease biology likely from these results.