Molecular mechanisms of autism as a form of synaptic dysfunction

Abstract

Autism spectrum disorders are a separate group of defects with a very high genetic component. Genetic screening has identified hundreds of mutations and other genetic variations associated with autism, and bioinformatic analysis of signaling pathways and gene networks has led to understanding that many of these mutational changes are involved in the functioning of synapses. A synapse is a site of electrochemical communication between neurons and an essential subunit for learning and memory. Interneuronal com municative relationships are plastic. The most promin ent forms of synaptic plasticity are accompanied by changes in protein biosynthesis, both in neuron body and in dendrites. Protein biosynthesis or translation is a carefully regulated process, with a central role played by mTOR (mammalian or mechanistic target of rapamycin). Normally mTORregulated translation is slightly inhibited, and in most cases mutational damage to at least one of the links of the mTOR sig naling pathway, increases translation and leads to impaired synaptic plasticity and behavior. Deregula tion of the local translation in dendrites is connected with the following monogenic autism spectrum disorders: neurofibromatosis type 1, Noonan synd ro me, Costello syndrome, Cowden syndrome, tuberous sclerosis, fragile X chromosome, syndrome, and Rett syndrome. The review considers the most important mutations leading to monogenic autism, as well as the possibility of a mechanismbased treatment of certain disorders of the autism spectrum.

On the dynamical aspects of local translation at the activated synapse

“…Today, there is strong evidence that rapid and well-coordinated changes in the quantitative and qualitative aspects of proteins at the synapse ensure its dynamic plasticity in response to external stimuli and underlie the learning and memory processes [ 1 , 3 , 12 , 21 – 24 ]. Disruption of the local translation control at synapse is associated with various neuropsychiatric diseases, including ASD (autism spectrum disorders) [ 6 , 7 , 25 , 26 ], epilepsy [ 4 , 5 ], Parkinson’s and Alzheimer’s diseases [ 5 , 27 , 28 ], which are characterized by imbalanced synaptic plasticity and lead to changes in behavior, cognitive abilities and memory. It is possible that synaptopathy, which occurs in multiple sclerosis, is associated with dysfunction of the regulatory components of local translation – mTOR signaling and FMRP [ 29 ], which regulates the efficiency of dendritic mRNA translation [ 12 ].…”

A Molecular Framework for Autistic Experiences: Mitochondrial Allostatic Load as A Mediator between Autism and Psychopathology

“…This relationship plays an important role in mediating the metabolic shift that is required to facilitate neurogenesis (262)(263)(264)(265)(266). Furthermore, both mTOR signaling (262,(267)(268)(269) and mitochondrial function (270)(271)(272)(273)(274)(275) are essential for synaptic signaling, function and plasticity. In fact, preclinical data suggest that ELS impairs neuronal metabolism and synaptic plasticity via mTOR-dependent mechanisms (276,277).…”

A Molecular Framework for Autistic Experiences: Mitochondrial Allostatic Load as A Mediator between Autism and Psychopathology

“…Neuronal differentiation is closely tied to metabolic state, which is coupled to, and regulated by, mTOR signaling and this relationship plays an important role in mediating the metabolic shift that is required to facilitate neurogenesis (246)(247)(248). Notably, both mTOR signaling (246,(249)(250)(251) and mitochondrial function (252)(253)(254)(255)(256)(257) are essential for synaptic signaling, function and plasticity. Wang et al, (2020) recently showed that ELS impaired synaptic plasticity by inhibiting mTOR signaling in the mouse hippocampus, resulting in increased anxiety-like behavior and cognitive impairments (258) while Sanchez et al, (2022) also demonstrated that ELS induced hyperactivation of the mTOR complex and reduced oxidative metabolic capacity in the amygdala (259).…”