pannexin-1 inhibitor Although ASD is considered one of the m

Although ASD is considered one of the most heritable neurodevelopmental disorders (El-Fishawy & State, 2010; Geschwind, 2011) and majority of the research on ASD has focused on the genetics of the disorders (Autism Genome Project, C, 2007; Buxbaum & Hof, 2011), single causative gene anomalies account for only a small proportion of ASD cases (Herbert, 2010; Landrigan et al., 2012). To date, inheritance of multiple gene variants, rare de novo single gene mutations and copy number variants have been proposed to be liable for ASD. In addition, a multitude of environmental risk factors have been proposed to contribute to the development of ASD (Herbert, 2010). Prenatal environmental conditions, such as maternal infections during pregnancy, have been linked to social communication difficulties in children with ASD-associated CNVs (Vijayakumar & Judy, 2016). Other environmental factors that have been proposed to interact with risk genes include preterm birth, folate deficiency, and exposure to certain toxins (Vijayakumar & Judy, 2016). One of these risk factors is lead exposure, which can cause dose-dependent changes in DNA methylation (Dosunmu et al., 2012), and among the hypomethylated genes caused by lead exposure, some affect pannexin-1 inhibitor cytoskeleton (Senut et al., 2014). Genes associated with autism are listed at publicly accessible websites SFARI Gene (https://gene.sfari.org/database/human-gene/) and AutismKB (http://autismkb.cbi.pku.edu.cn/index.php). In this review, we evaluate the current literature from SFARI listed genes, which encode proteins that regulate actin dynamics and have been linked with autism (Table 1, Table 2). The review aims to discuss the current literature to unravel whether the actin regulators encoded by ASD-associated genes regulate synaptic structure and function, and if yes, how? Additionally, the review aims to identify any common pathways on synaptic or actin regulation among these ASD-associated actin regulators.
The role of actin cytoskeleton and actin binding proteins on the imbalanced spine formation and plasticity in ASD Although a wide range of autism-associated genes has been identified, it is becoming increasingly evident that many of these genes converge into common cellular pathways associated with neurite outgrowth, synaptogenesis, synaptic plasticity and spine stability, which together regulate the structural stability of neurons. Actin is the building block of cells and regulates the shape and density of dendritic spines (Hotulainen & Hoogenraad, 2010). Perturbing actin cytoskeleton and its regulators can lead to an imbalance in cytoskeleton dynamics, which in turn, can cause alterations in dendritic spine size, shape and number, as well as neural arborization. The correct morphology of synapses is key to the formation of functional neuronal circuitry and deficits in the structural stability of dendritic spines have been reported in several neurological disorders, including fragile X syndrome (FXS) (Scotto-Lomassese et al., 2011), schizophrenia (Cahill et al., 2012; Kalus et al., 2000) and autism (Raymond et al., 1996).
Treatment Genetic and pharmacological interventions in mouse models of ASD, including TSC (Auerbach et al., 2011), FXS (Bhakar et al., 2012), Rett syndrome (Guy et al., 2007; Giacometti et al., 2007) and Angelman syndrome (van Woerden et al., 2007), as well as in Shank2−/− mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene (Won et al., 2012), have shown promise in improving ASD phenotypes, offering hope for the development of therapeutics for ASD. Autism-like social deficits and repetitive behaviors have been rescued by targeting actin regulators in Shank3-deficient mice (Duffney et al., 2015). This autism-mouse model shows significantly diminished NMDA receptor function and synaptic distribution in the prefrontal cortex, as well as a marked loss of cortical actin filaments associated with reduced Rac1/PAK activity and increased cofilin activity. The social deficits and NMDA receptor hypofunction displayed by the mice was rescued by inhibiting cofilin activity or by activating Rac1 (Duffney et al., 2015). In agreement with these results, treatment of Shank2−/− mice with 3-cyano-N-1,3-diphenyl-1H-pyrazol-5-yl benzamide (CDPPB), which increases the responsiveness of mGluR5 to glutamate and enhances NMDA receptor function (Gregory et al., 2011), markedly improves autistic-like social behavior (Won et al., 2012). Targeting the deficits of actin cytoskeleton in the most common inherited form of autism and intellectual disability, FXS, has also shown promise (Dolan et al., 2013). Fragile X syndrome is the most common type of inherited mental retardation caused by the absence of FMRP protein, a RNA-binding protein implicated in the regulation of mRNA translation and transport, leading to protein synthesis. The Fmr1 knockout mice display hyperactivity, seizures, repetitive behaviour, and abnormal spine densities similarly to the human condition. Among many other proteins, FMRP negatively regulates expression of Rac1 and pharmacological manipulation of Rac1 partially reverses the altered long-term plasticity seen in Fmr1 KO mice (Bongmba et al., 2011). Accordingly, by inhibiting the Rac1 effector, group I p21-activated kinase (PAK) protein, which regulates spines through modulation of actin cytoskeleton dynamics, with a drug called FRAX486, the dendritic spine phenotype is reversed in Fmr1 KO mice (Dolan et al., 2013). PAK inhibition also rescues seizures and behavioural abnormalities such as hyperactivity and repetitive movements, indicating that targeting spine abnormalities can also treat neurological and behavioural symptoms (Dolan et al., 2013). Remarkably, Dolan and colleagues (Dolan et al., 2013) showed in 2013 that a single administration of FRAX486 is sufficient for the phenotype rescue in adult Fmr1 knockout mice, demonstrating that a postdiagnostic therapy could be possible for FXS adults.