Cellular and molecular mechanisms of neurodevelopmental disorders

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Neurodevelopmental disorders are a group of affections whose onset and clinical expression occur during infancy/childhood or adolescence, and for which disease mechanisms are still largely a mystery. These disorders include autism and schizophrenia spectrum disorders, intellectual disability, and attention deficit hyperactivity disorder. Some of them are the focus of this issue. Neurodevelopmental disorders have a strong genetic basis, but causal environmental factors have also been identified. These predisposition factors may interact during brain developmental vulnerability windows to cause disease in ways that are not clearly understood yet (Maynard et al., 2001; Rappoport et al., 2012; Farrell et al., 2015; Charman and Chakrabarti 2016; Davis et al., 2016).
Brain development is a continuous highly regulated process with pre‐ and postnatal windows of high vulnerability (Marco et al., 2011; Silbereis et al., 2016). Hence, a limited insult during one of these windows may alter the trajectory of brain development in individuals with susceptible genomes causing subtle abnormalities and conferring a predisposition to develop, for example, schizophrenia spectrum disorders in late adolescence/young adulthood (Maynard et al., 2001; Fatemi and Folsom, 2009; Rappoport et al., 2012; Piper et al., 2012; Davis et al., 2016). These windows of susceptibility may explain why neurodevelopmental disorders sometimes have overlapping clinical features, commonly co‐occur, and why the same mutation may end up associated with different mental illnesses. In fact, most neurodevelopmental disorders do not have a bona fide gene (Chisholm et al., 2015; Farrell et al., 2015; O'Donovan and Owen, 2016).
The complexity of these affections often leaves physicians fumbling in the dark when diagnosing cases that do not fit precisely into categorical diagnoses. At the same time, spotty knowledge about disease mechanisms hinders and slows down the development of better‐targeted therapeutic molecules or interventions. Even though our cellular and molecular understanding of neurodevelopmental disorder pathogenesis is still incomplete, we believe that the recent advancements in genomics, patient‐derived neuronal cultures, and novel mouse genetic models have positioned the field at the cusp of revolutionary developments in diagnosis and treatment. We sought to assemble an “in focus” issue to present the foundations for this optimistic view of the future. This issue covers some of the work done and in progress on neurodevelopmental disorders, their aetiology, underlying mechanisms, and potential therapeutics.
The biological plausibility of some experimental models might be questionable or has not been fully explored, however, several reproduce brain morphological abnormalities and the associated behavioural and cognitive deficits described in affected individuals. Thus, in vitro, ex vivo and in vivo models made possible to study discrete aspects of the pathophysiological mechanisms underlying developmental neuropsychiatric disorders, otherwise, limited to post‐mortem samples obtained after years of disease and treatments. Albeit, animal models have proven valuable to examine the consequence of aberrant expression of specific genes associated with neurodevelopmental disorders, still no single model completely recapitulates human disease presentation. Hence, the usage of more than one model is a necessity.
At present, human induced pluripotent stem cells (hIPSCs) derived from individuals with specific mental illnesses are regarded as highly promising to study the aetiopathophysiology of neurodevelopmental disorders. As reviewed by Dr Zhexing Wen in this issue (2017), hIPSCs represent a big step forward in comparison to classical in vitro models, and offer a highly controlled method not only to study disease mechanism(s), but to also test potential new drug treatments, which are in critical need. hIPSCs can be differentiated into different neuronal cell populations relevant to a specific disease, and should faithfully recapitulate human pathology, furthering our knowledge on specific cellular and molecular defects, a great aid to concurrent preclinical animal studies, human genetic and imaging studies.
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