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Genetics Studies Indicate That Neural Induction and Early Neuronal Maturation Are Disturbed in Autism

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Genetics Studies Indicate That Neural Induction and Early Neuronal Maturation Are Disturbed in Autism View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector HYPOTHESIS AND THEORY ARTICLE published: 19 November 2014 CELLULAR NEUROSCIENCE doi: 10.3389/fncel.2014.00397 Genetics studies indicate that neural induction and early neuronal maturation are disturbed in autism Emily L. Casanova* and Manuel F. Casanova Department of Psychiatry and Behavioral Sciences, School of Medicine, University of Louisville, Louisville, KY, USA Edited by: Postmortem neuropathological studies of autism consistently reveal distinctive Andrea Barberis, Istituto Italiano di types of malformations, including cortical dysplasias, heterotopias, and various Tecnologia, Italy neuronomorphometric abnormalities. In keeping with these observations, we review here Reviewed by: that 88% of high-risk genes for autism influence neural induction and early maturation Yehezkel Ben-Ari, Institut National de la Santé et de la Recherche of the neuroblast. In addition, 80% of these same genes influence later stages of Médicale, France differentiation, including neurite and synapse development, suggesting that these gene Enrica Maria Petrini, Istituto Italiano products exhibit long-lasting developmental effects on cell development as well as di Tecnologia, Italy elements of redundancy in processes of neural proliferation, growth, and maturation. *Correspondence: We also address the putative genetic overlap of autism with conditions like epilepsy and Emily L. Casanova, Department of Psychiatry and Behavioral Sciences, schizophrenia, with implications to shared and divergent etiologies. This review imports University of Louisville, 511 S. Floyd, the necessity of a frameshift in our understanding of the neurodevelopmental basis of MDR #122, Louisville, KY 40202, autism to include all stages of neuronal maturation, ranging from neural induction to USA synaptogenesis. e-mail: [email protected]; [email protected] Keywords: neuropathology, neurogenesis, epilepsy, schizophrenia, neocortex, synapse, dendrite INTRODUCTION associated with savantism, are more frequently spared (Treffert, Neuroblasts require precise extrinsic and intrinsic signals to 2010). acquire their unique, semi-predetermined identities. For instance, Reflective of the large-network incoordination in autism, neu- the complement of developmental signals that produce a sero- ropathological studies performed over the last several decades tonergic neuron in the raphe nucleus are different from those indicate that the brains of autistic individuals are characterized that produce dopaminergic neurons in the substantia nigra, lead- by heterogeneous dysgeneses or malformations, ranging from ing genetically similar neuroblasts along divergent paths (Hynes subtler dysplasias affecting lateral cell dispersion within mini- and Rosenthal, 1999). Though signals for growth and differen- columns, to the more obvious heterotopias which can sometimes tiation may funnel through similar pathways for all neurons, be seen on magnetic resonance imaging (MRI) as Unidentified such as the Wingless Integration Site (Wnt), Hedgehog, and Bright Objects (UBO) (Nowell et al., 1990; Casanova et al., 2002; Transforming Growth Factor-β (TGF-β) families, the effectors Wegiel et al., 2010). At the microscopic level, altered cell mor- that regulate these pathways can vary considerably from one brain phologies (e.g., reduced soma size) are also often noted (Casanova structure to the next, allowing the creation of distinct boundaries et al., 2002). and the refinement of cellular identities (Wolpert and Kerszberg, Across a series of three separate studies since 1998, various 2003). From this basic arrangement arise not only variations in neuropathologists have found direct evidence of neocortical dys- morphology but function, and together these different neuronal genesis in autism ranging from 92 to 100% of their subjects, species commune to produce a finely-tuned, well-coordinated indicating that disturbances to early neocortical development are network of cells. likely fundamental to the conditions (Bailey et al., 1998; Wegiel However, in autism spectrum conditions (referred to here et al., 2010; Casanova et al., 2013). Wegiel et al. also reported collectively as “autism”), neuroimaging and electrophysiology that subcortical, periventricular, hippocampal, and cerebellar het- suggest that these networks are prone to disruption and that erotopias were present in 31% of cases, meanwhile 62% of their disparate cognitive modules communicate comparatively asyn- subjects exhibited cerebellar dysgenesis. These types of corti- chronously (Just et al., 2007; Sokhadze et al., 2009). In sup- cal, subcortical, and periventricular malformations are strongly port, many autistic people, for instance, have difficulties in linked with epileptic susceptibility in the general population and processing vision and speech simultaneously, two faculties probably explain the high rates of epilepsy in autism (Raymond which are normally well-intertwined for most people (Murray et al., 1995). et al., 2005; Stevenson et al., 2014). In addition, cogni- Considerable research energies have been devoted to the study tive tasks that require the coordination of large networks of of autism at the level of the neurite and synapse (Auerbach et al., cells, such as socialization, language, and executive functions, 2011). It therefore becomes a challenge to rectify what appears to are usually the most impaired in the conditions; meanwhile, be conflicting evidence arising from the fields of neuropathology those tasks that necessitate smaller networks, skills sometimes andgenetics.Anumberofstudieshavesuggestedthatneurite- Frontiers in Cellular Neuroscience www.frontiersin.org November 2014 | Volume 8 | Article 397 | 1 Casanova and Casanova Neuronal maturation in autism and synapse-associated gene products, such as Contactin- roles for each gene in neurogenesis, neural induction, and neu- associated Protein-like 2 (Cntnap2), Neuroligin-4, X-linked roblast differentiation. In order to better summarize our find- (Nlgn4x), and Neurexin-1-alpha (Nrxn1), may in fact be involved ings, we applied a semi-quantitative rating system to each gene, in earlier stages of differentiation than typically acknowledged, ranging from “0” which indicates that there is no known rela- resulting in defects of migration and other indications of dis- tion between the gene product function and neuroblast devel- turbance to pre-migratory cell fate determination (Peñagarikano opment, to “3” in which there is a confirmed direct rela- et al., 2011; Shi et al., 2013; Zeng et al., 2013). We have there- tionship, the latter most frequently manifest as either prema- fore considered the possibility that some genes expressed dur- ture or delayed neurogenesis (see Figure 1). We also addressed ing early stages of neuronal development may continue to have each gene’s involvement in either neuritogenesis or synapto- rippling effects on later stages of differentiation, permanently genesis. If abnormal branching, synaptomorphology, or synap- perturbing neuronal maturation when their gene products are tophysiology were reported in human cases, animal models, impaired. Other genes may also express considerable functional or in vitro studies for a specific gene, this was considered redundancy at numerous stages of cell growth and develop- a“hit.” ment, likewise leading to shared disturbances in neurogenesis In addition to reviewing the various functions of each and neurite extension or synaptogenesis. Thus, we have gathered gene product, we also studied their involvements in epilepsy a core set of idiopathic and syndromic high-risk autism genes and schizophrenia. As discussed earlier, seizure disorder occurs in order to perform an in-depth review of their myriad cellu- frequently in autism, and within the general epileptic pop- lar functions in early brain development and determine whether ulation dyplasias, heterotopias, and ectopias are often seats commonalities exist that may explain the broad range of findings of epileptiform activity, suggesting links in the etiologies of in autism. autism and epilepsy (Avoli et al., 1999). In order to deter- mine a relationship between epilepsy and a given gene, the FUNCTIONAL OVERLAP OF CORE AUTISM GENES literature was searched for indications of the gene’s involve- We have performed an in depth review of the literature sur- ment in epileptic susceptibility; modest overlap was consid- rounding a core set of 197 high-risk autism-related genes. Our ered a “hit.” Likewise, gene overlap between the core set and list was compiled from the SFARI and AutismKB databases. schizophrenia risk genes was assessed using the SzGene database We selected the “Syndromic,” “High Confidence,” and “Strong and considered a “hit” if contained therein (Allen et al., Candidate” categories from the SFARI database and the core and 2008). syndromic datasets (version 2) from the AutismKB database in According to our review, 88% of core genes fell within the 2– order to derive our final core set (Banerjee-Basu and Packer, 3 rating categories, while only 12% fell within the 0–1 rating, 2010; Xu et al., 2012; databases accessed on 6/15/14). The lit- suggesting that the vast majority of high-risk autism genes help erature was then reviewed in depth, focusing on regulatory to regulate neural induction and early neuroblast differentiation FIGURE 1 | Bar graph showing the number of high-risk autism core genes that fall within a given rating (0–3), with criteria
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