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    • Nutritional factors affecting ASD have also

    2023-09-15

    Nutritional factors affecting ASD have also recently received attention. An increase in postsynaptic zinc (Zn) level induced by clioquinol (a Zn chelator and ionophore), and the subsequent activation of NMDA receptors through the tyrosine kinase Src, rescued social interaction in Shank2−/− mice (Lee et al., 2015). Shank3 mutations and large duplications both cause a spectrum of neuropsychiatric disorders, indicating that the correct protein expression level is critical for normal brain function. Shank3 transgenic mice, modeling a human SHANK3 duplication, exhibit manic-like behavior and seizures consistent with a synaptic excitatory/inhibitory imbalance, similar to the symptoms of two hyperkinetic disorder patients carrying the smallest SHANK3-spanning duplications reported so far (Han et al., 2013). SHANK3 was found to directly interact with Arp2/3 and to increase F-actin levels in the Shank3 transgenic mice, and treating the mice with the mood-stabilizing drug valproate, but not lithium, ameliorated the manic-like behavior (Han et al., 2013). Consistent with previous results showing that NMDA receptor membrane delivery and stability depend on the integrity of LCL161 cytoskeleton (Duffney et al., 2013), these findings further highlight that the dysregulation of synaptic actin filaments and the loss of synaptic NMDA receptors contribute to the manifestation of autism-like phenotypes, and thus provide strategies for the treatment of autism (Duffney et al., 2015). Drug trials in human patients have also taken place. One example is the recent therapeutic study on TSC patients with autistic symptoms (Kilincaslan et al., 2017). TSC disease is caused by loss-of-function mutations in TSC1 or TSC2 genes (Feliciano et al., 2013; DiMario et al., 2015), which code the proteins TSC1 and TSC2. TSC1 and TSC2 bind together to form a complex that inhibits mTOR, which controls translation, proliferation, and cell growth (Curatolo et al., 2010). Treating children and adolescent TSC patients displaying emotional and behavioral symptoms and refractory epilepsy with everolimus, an inhibitor of mTOR, produced beneficial effects in relation to the autistic, ADHD, and depressive symptoms, as well as controlling the seizures (Kilincaslan et al., 2017). Consistent with the hypothesis that excessive metabotropic glutamatergic signaling in autism may cause some of the core symptoms of the disorder, several studies using mGluR5 antagonists in animal models of autism have reported beneficial behavioral improvements, with varying side effects in mice (Mehta et al., 2011; Burket et al., 2011; Silverman et al., 2010). The mGluR5 antagonists that have been evaluated for efficacy in FXS are an example of therapeutics that have been developed to treat a specific disorder, but that might have more general applicability. However, challenges to translate results from FXS animal models to humans include uncertainties regarding optimal patient selection, age of treatment onset, dosages and durations of treatment, differences in pharmacokinetics and pharmacodynamics, dose-limiting side effects, and biomarkers of CNS improvement. In recent years, there have been some preliminary results to indicate that targeted treatment with mGluR5 antagonists may be beneficial for autistic children (Gurkan & Hagerman, 2012). However, to date, there are no reports of successful randomized, double-blind, placebo-controlled mGluR5 antagonist drug trials on humans. Defining how different ASD-associated mutations disrupt synaptic structure and function may be crucial for the development of therapeutics that target a particular molecular defect. Understanding the molecular basis of ASD will hopefully allow rational development of therapies for a spectrum of autistic disorders.
    Final words Based on this review, we draw three main conclusions. First, many actin regulators associated with ASDs have a role in the regulation of synaptic structure and/or function, suggesting that a perturbation in the interplay between the PSD and dendritic spine actin cytoskeleton is one of the key cellular processes in ASD pathology. Actin regulators such as SHANKs, can also act as synaptic scaffolding platforms, or they can link postsynaptic scaffolding proteins, such as PSD-95 to the actin cytoskeleton, as in the case of IRSp53/BAIAP2. Alternatively, proteins can mediate the effects of various receptors on the cytoskeleton; DISC1 mediates the effects of NMDA receptors on Rac1 signaling, whereas α-actinin-4 facilitates mGluR-induced actin remodeling (Kalinowska et al., 2015). Furthermore, some proteins, such as gelsolin and α-actinin-4, can be regulated by a neuronal activity-induced increase in postsynaptic Ca concentration. Defective stabilization of neuronal structures may also be important in ASD pathology (Lin et al., 2016) as many associated proteins link actin cytoskeleton either to plasma membrane (Irsp53, α-actinin-4) or to the extracellular matrix (dystrophin and utrophin) or regulate the connection between actin filaments and extracellular matrix (SHANKs) (Lilja et al., 2017).