Engrailed 2 deficiency and chronic stress alter avoidance and motivation behaviors

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.

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Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications

Jiang

Lin

Long

et al. 2022

Sig Transduct Target Ther

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Dopamine Dysregulation in Reward and Autism Spectrum Disorder

Blum,

Bowirrat,

Sunder

et al. 2024

Brain Sciences

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Autism spectrum disorder (ASD) is primarily characterized by core deficits in social skills, communication, and cognition and by repetitive stereotyped behaviors. These manifestations are variable between individuals, and ASD pathogenesis is complex, with over a thousand implicated genes, many epigenetic factors, and multiple environmental influences. The mesolimbic dopamine (DA) mediated brain reward system is held to play a key role, but the rapidly expanding literature reveals intricate, nuanced signaling involving a wide array of mesolimbic loci, neurotransmitters and receptor subtypes, and neuronal variants. How altered DA signaling may constitute a downstream convergence of the manifold causal origins of ASD is not well understood. A clear working framework of ASD pathogenesis may help delineate common stages and potential diagnostic and interventional opportunities. Hence, we summarize the known natural history of ASD in the context of emerging data and perspectives to update ASD reward signaling. Then, against this backdrop, we proffer a provisional framework that organizes ASD pathogenesis into successive levels, including (1) genetic and epigenetic changes, (2) disrupted mesolimbic reward signaling pathways, (3) dysregulated neurotransmitter/DA signaling, and finally, (4) altered neurocognitive and social behavior and possible antagonist/agonist based ASD interventions. This subdivision of ASD into a logical progression of potentially addressable parts may help facilitate the rational formulation of diagnostics and targeted treatments.

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Engrailed 2 deficiency and chronic stress alter avoidance and motivation behaviors

Cited by 2 publications

References 83 publications

Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications

Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications

Dopamine Dysregulation in Reward and Autism Spectrum Disorder

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