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Specific form of autism caused by neuronal alteration

Researchers have identified a form of autism that is caused by the presence of an excessive number of synapses in the cerebral cortex.

Autism and neuronal alterations

Autism spectrum disorder (ASD) is a developmental disorder that impacts communication and behaviour. ASD is characterised by a complex aetiology and phenotypic presentation. There are multiple syndromic forms of ASD that have been found to be the result of mutations in genes that affect translational control, protein synthesis and the structure, transmission and plasticity of synapses. Consequently, these observations have led to the hypothesis that dysfunctional synaptic pruning and homeostasis may be a key contributor to ASD pathology.

This has been supported by post-mortem histological examinations that have shown the presence of increased dendritic spine density in brain tissue. One study has suggested a link between post-mortem dendritic synaptic surplus in ASD and hyperactivity of the mammalian target of rapamycin (mTOR) pathway. mTOR is a key regulator of synaptic protein synthesis.

Several studies have also highlighted the presence of aberrant functional connectivity in ASD. These findings suggest that specific clinical manifestations of ASD could at least partly reflect interareal brain synchronisation. 

mTOR-related synaptic pathology

In a recent study, published in Nature, researchers explored whether there was a causal mechanistic link between mTOR-related synaptic pathology and aberrant functional connectivity alterations in ASD. They tested this hypothesis using resting-state fMRI, electrophysiology and in silico modelling in haploinsufficient tuberous sclerosis complex 2 mice (Tsc2+/−). This is a mouse line that mechanistically reconstitutes mTOR-dependent synaptic surplus that has previously been observed in post-mortem ASD investigations.

The team found that an excessive number of synapses produced dysfunction in brain circuits that are crucial for brain function and social communication. The researchers further demonstrated that this alteration could be linked to aberrant mTOR activity. This was confirmed by pharmacologically inhibiting mTOR-hyperactivity, which resulted in the number of synapses returning to physiological levels and the function and connectivity of circuits becoming completely restored.

Using machine-learning methods, the team then investigated whether this specific circuit dysfunction could be identified in publicly available brain scans of children with idiopathic autism. The activity was identified in a subgroup of scans that exhibited hyperconnectivity similarly to the murine models. In addition, they showed that the identified circuital dysfunction could be mechanistically linked to aberrant mTOR activity.

Overall, these findings contribute to the complex aetiology that underpins autism. These findings may also help guide the development of future pharmacological treatments designed to correct these aberrations.

Alessandro Gozzi, coordinator of CNCS at IIT, said:

“Our results might help decode the mosaic of autism, which in fact is a heterogeneous group of problems and causes. The challenge that lies ahead of us is now the identification of all the remaining pieces of the autism mosaic, which might enable the future development of precision therapy targeted to specific subsets of autism.”

Image credit: canva