Autism spectrum disorder is typically diagnosed during the first 3 years of life, a period of extensive neurite formation, synaptogenesis and refinement (Huttenlocher and Dabholkar, 1997; Zoghbi and Bear, 2012; Stamou et al., 2013; Mc Gee et al., 2014). Indeed, brain imaging studies from individuals with ASD and anatomical measurements of neuronal structure in post-mortem tissues exhibit differences in neuronal connectivity derived from the disruption of neurite outgrowth, synapse formation and stabilization (Raymond et al., 1996; Hutsler and Zhang, 2010; Penzes et al., 2011). doi: 10.1002/ajmg.b.30493 Pub Med Abstract | Cross Ref Full Text | Google Scholar Buxbaum, J. Neurites initially exhibit frequent branch additions and retractions. Once dendrite arbors are established, productive synapse formation later in life and the accompanying activation of post-synaptic signaling machinery promotes arbor stability (Dailey and Smith, 1996; Wu and Cline, 1998; Rajan et al., 1999; Wong et al., 2000; Cline, 2001; Niell et al., 2004).
Although knockout, knockin, or transgenic approaches of autism-risk genes in animal models have demonstrated some of the autistic-like behaviors (Kazdoba et al., 2016), the limitation of the number of genes being manipulated in animals makes it difficult to recapitulate the human condition experimentally. The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition. These brain regions are often characterized with neuroanatomical irregularities in ASD (Donovan and Basson, 2016). The autism sequencing consortium: large-scale, high-throughput sequencing in autism spectrum disorders. doi: 10.1016/j.neuron.20 Pub Med Abstract | Cross Ref Full Text | Google Scholar Camacho, A., Simon, R., Sanz, R., Vinuela, A., Martinez-Salio, A., and Mateos, F. Cognitive and behavioral profile in females with epilepsy with PDCH19 mutation: two novel mutations and review of the literature. The defective regulation for structural stability of neurons may be one of the underlying mechanisms that contribute to the anatomical changes in ASD. Animal studies of these genes further identify several specific cellular pathways during brain development that are vulnerable in ASD, including the disruption of neurite outgrowth, dendritic spine formation, and synaptic function (Figure 1) (Walsh et al., 2008; Bourgeron, 2009; Hussman et al., 2011; Penzes et al., 2011; Zoghbi and Bear, 2012; Ebert and Greenberg, 2013; Stamou et al., 2013; Bernardinelli et al., 2014; De Rubeis et al., 2014; Pinto et al., 2014; Phillips and Pozzo-Miller, 2015). Differences in environment as well as the presence of multiple gene mutations occurring in the same individual with autism complicate studies of the relationship between each gene and the phenotype observed. However, because similar cellular pathways (e.g., neurite outgrowth) are altered in different affected individuals, we can potentially develop therapeutic interventions to help mitigate the autism phenotypes. Diagram of autism-risk genes implicated in regulating the structural stability of neurons. The autism simplex collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses. doi: 10.1186/2040-2392-5-34 Pub Med Abstract | Cross Ref Full Text | Google Scholar Buxbaum, J. Each circle represents a cellular pathway to regulate the structural stability of neurons, including neurite outgrowth (red), dendritic spine or synapse formation (blue), and synaptic plasticity (gold). D., Cai, G., Chaste, P., Nygren, G., Goldsmith, J., Reichert, J., et al. Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. Alterations in neuronal structures in different brain regions have been reported in ASD individuals, including increased dendritic spine density in cortical pyramidal neurons (Hutsler and Zhang, 2010; Tang et al., 2014) as well as stunting of dendritic branching in the hippocampus (Raymond et al., 1996; Bauman and Kemper, 2005). In addition, subcortical band heterotopia, representing alterations in cell migration has also been found in a child with ASD (Beaudoin et al., 2007). doi: 10.1016/j.yebeh.20 Pub Med Abstract | Cross Ref Full Text | Google Scholar Camacho-Garcia, R. The summaries of autism-risk genes that affect each cellular pathway can be found in Tables 1–3. During development, neurite outgrowth and synapse formation are dynamic processes and their maturation is mutually dependent on proper guidance. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations.