Abstract
Autism spectrum disorders (ASDs) are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases.
Highlights
Autism spectrum disorders (ASDs) encompass a group of neurodevelopmental disorders which are of different etiologies and characterized by impairments in socialization and communication, abnormalities in language development, restricted interests, and repetitive and stereotyped behaviors (Mefford et al, 2012; Zoghbi and Bear, 2012; Murdoch and State, 2013; Anagnostou et al, 2014b; Lai et al, 2014)
Jun N-terminal kinase (JNK) activity is upregulated in synapses of Fmr1 knockout mice, and inhibition of JNK with SP600125 decreased elevated postsynaptic protein synthesis in these mice, suggesting that JNK could be a key signaling downstream of Metabotropic glutamate receptors (mGluRs) in regulating fragile X mental retardation protein (FMRP)-dependent protein synthesis and may provide a strategy to restore the deficits in fragile X syndrome (Schmit et al, 2013)
The translational success stories in fragile X and Rett syndromes indicates that the effectiveness of targeted treatments in animal models can turn into clinical efficacy in humans, provided that studies are well designed, the models are reliable and robust, and that preclinical outcome measures are relevant to patients (Anagnostou, 2012; Lipton and Sahin, 2013; Castro et al, 2014; Khwaja et al, 2014)
Summary
Autism spectrum disorders (ASDs) encompass a group of neurodevelopmental disorders which are of different etiologies and characterized by impairments in socialization and communication, abnormalities in language development, restricted interests, and repetitive and stereotyped behaviors (Mefford et al, 2012; Zoghbi and Bear, 2012; Murdoch and State, 2013; Anagnostou et al, 2014b; Lai et al, 2014). It has been shown that 5-HT7 receptor (agonist 8-OH-DPAT) activation could reverse mGluR-induced AMPA receptor internalization and correct excessive mGluRLTD in hippocampal neurons of Fmr1 knockout mice, suggesting that 5-HT receptors may represent a novel therapeutic target for fragile X syndrome (Costa et al, 2012).
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