Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications

Abstract

Autism spectrum disorder (ASD) is a prevalent and complex neurodevelopmental disorder which has strong genetic basis. Despite the rapidly rising incidence of autism, little is known about its aetiology, risk factors, and disease progression. There are currently neither validated biomarkers for diagnostic screening nor specific medication for autism. Over the last two decades, there have been remarkable advances in genetics, with hundreds of genes identified and validated as being associated with a high risk for autism. The convergence of neuroscience methods is becoming more widely recognized for its significance in elucidating the pathological mechanisms of autism. Efforts have been devoted to exploring the behavioural functions, key pathological mechanisms and potential treatments of autism. Here, as we highlight in this review, emerging evidence shows that signal transduction molecular events are involved in pathological processes such as transcription, translation, synaptic transmission, epigenetics and immunoinflammatory responses. This involvement has important implications for the discovery of precise molecular targets for autism. Moreover, we review recent insights into the mechanisms and clinical implications of signal transduction in autism from molecular, cellular, neural circuit, and neurobehavioural aspects. Finally, the challenges and future perspectives are discussed with regard to novel strategies predicated on the biological features of autism.

mTOR Signaling Disruption and Its Association with the Development of Autism Spectrum Disorder

“…Neurexins and neuroligins are presynaptic and postsynaptic binding proteins that coordinate to form transsynaptic complexes. These proteins directly facilitate synapse formation and stabilization [ 119 ]. Neuroligins like NLGN-1, NLGN-3, and NLGN-4 localize to the glutamate postsynaptic membrane, whereas NLGN-2 localizes primarily to GABA synapse.…”

“…Different therapeutic approaches have been used to restore E/I imbalance, such as treatment with mGluR5 antagonist, NMDAR agonist, and GABAR agonist. Investigation in rodent models from FXS have revealed variations in GABA-mediated synaptic transmission, further suggesting therapeutic potential of GABA receptor agonism in FXS [ 119 ].…”

Dendritic spine and synapse pathology in chromatin modifier-associated autism spectrum disorders and intellectual disability

“…Neurodevelopmental disorders are a complex disease caused by a combination of different etiological factors that include abnormal molecular signaling pathways, synapses, or brain connections ( Jiang et al, 2022 ). Clinical trials of pharmacological interventions for neurodevelopmental diseases are challenging and at an early stage, with questions to be resolved about outcome measures, age of treatment onset, and duration of treatment ( Jacquemont et al, 2018 ; Rhine et al, 2019 ; Basilicata et al, 2021 ).…”

“…Synaptic deficits may trigger early events in the pathogenesis of neurodevelopmental disorders ( Taoufik et al, 2018 ; Linda et al, 2022 ). Many synaptic proteins are part of the pathogenic risk factors of ASD ( Jiang et al, 2022 ). Also, ID target genes such as the Fragile X Messenger Ribonucleoprotein 1 ( FMR1 ) and Cullin 4B ( CUL4B ) encode or regulate essential synaptic proteins ( Nakagawa and Xiong, 2011 ; Prieto et al, 2020 ).…”

SCGN deficiency is a risk factor for autism spectrum disorder

“… 4 In addition to these core symptoms, autistic individuals can develop delayed development, intellectual disability, anxiety, depression, and gastrointestinal and immune conditions. 5 It is estimated that ASD affects 1–2% of all children, causing significant social and economic burdens for society. 6 The heterogeneous clinical features of ASD have greatly challenged the development of effective treatments.…”