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AUTISM AND CHOLESTEROL METABOLISM Autism spectrum disorders (ASDs) are a group of developmental psychiatric disorders characterized by impaired social interaction and communication, and by restricted, repetitive and stereotyped behaviors and interests (Zoghbi and Bear, 2012; Ebert and Greenberg, 2013; Huguet et al., 2013). Since the features of ASDs usually manifest at the early childhood when sensory experience is modifying the development and balance of excitatory and inhibitory synapses, it has been hypothesized that ASDs may be due to the disruption of experience dependent synaptic development and function, resulting in an imbalance between excitation and inhibition in brain (Auerbach et al., 2011; Zoghbi and Bear, 2012; Delorme et al., 2013; Wang and Doering, 2013). Although genetic causes have been identified in many individuals with ASDs, the details about how those causal genes converge on common pathways to alter synaptic homeostasis in ASDs still need to be investigated. Recently, Buchovecky et al. described disturbances in cholesterol homeostasis in animal model of the ASD Rett syndrome (RTT), giving rise to an exciting prospect that changes in cholesterol metabolism might underlie the development of ASDs (Buchovecky et al., 2013). Cholesterol, an essential cell membrane component, influences the establishment and maintenance of synaptic connection and glial cell development in the nervous system. Balanced cholesterol homeostasis is an important aspect of nervous system function (Mauch et al., 2001; Pfrieger, 2003; Linetti et al., 2010; Pfrieger and Ungerer, 2011; Mathews et al., 2014) (Figure 1A). Perturbed cholesterol homeostasis can affect neural development and synaptogenesis and result in synaptic dysfunction, thus may lead to disorders of nervous system (Simons and Ehehalt, 2002; Linetti et al., 2010; Pani et al., 2010; Karasinska and Hayden, 2011). Evidence from patients indicates that cholesterol homeostasis could be altered in autistic disorders. The Smith-Lemli-Opitz Syndrome (SLOS), a genetic condition of impaired cholesterol biosynthesis due to mutations of the 7-dehydrocholesterol reductase gene (DHCR7), has been found to be associated with autism, supporting genetic defects in cholesterol metabolism can cause autism (Sikora et al., 2006; Bukelis et al., 2007; Diaz-Stransky and Tierney, 2012). Abnormal cholesterol metabolism has also been observed in patients with the ASD Asperger syndrome and other nonsyndromic ASDs, suggesting different abnormalities of cholesterol metabolism may exist in ASDs (Tierney et al., 2006; Dziobek et al., 2007). However, little is known about the mechanisms that mediate the abnormal cholesterol metabolism in these ASD conditions. RTT is caused largely by mutations in the X-linked methyl CpG-binding protein 2 gene (MECP2) (Baker et al., 2013; Lyst et al., 2013; Xu and PozzoMiller, 2013). In Mecp2 mutant mice, Buchovecky et al. found that the expression of genes (Hmgcr, Sqle and Cyp46a1) which encode key enzymes (3-hydroxy-3methylglutaryl-CoA reductase, squalene epoxidase, CYP46A1) in the cholesterol metabolic pathway and cholesterol concentrations are altered in the brain in a development dependent manner (Buchovecky et al., 2013). Their study indicates that loss of Mecp2 disrupts cholesterol homeostasis, suggesting abnormal cholesterol metabolism might be involved in the pathogenesis of RTT (Nagy and Ackerman, 2013). It thus links the autism associated gene to cholesterol metabolism, providing further insights into the relationship between cholesterol metabolism and ASDs.

Lipid rafts: a signaling platform linking cholesterol metabolism to synaptic deficits in autism spectrum disorders