mTOR-Dependent Spine Dynamics in Autism

Abstract

Autism Spectrum Conditions (ASC) are a group of neurodevelopmental disorders characterized by deficits in social communication and interaction as well as repetitive behaviors and restricted range of interests. ASC are complex genetic disorders with moderate to high heritability, and associated with atypical patterns of neural connectivity. Many of the genes implicated in ASC are involved in dendritic spine pruning and spine development, both of which can be mediated by the mammalian target of rapamycin (mTOR) signaling pathway. Consistent with this idea, human postmortem studies have shown increased spine density in ASC compared to controls suggesting that the balance between autophagy and spinogenesis is altered in ASC. However, murine models of ASC have shown inconsistent results for spine morphology, which may underlie functional connectivity. This review seeks to establish the relevance of changes in dendritic spines in ASC using data gathered from rodent models. Using a literature survey, we identify 20 genes that are linked to dendritic spine pruning or development in rodents that are also strongly implicated in ASC in humans. Furthermore, we show that all 20 genes are linked to the mTOR pathway and propose that the mTOR pathway regulating spine dynamics is a potential mechanism underlying the ASC signaling pathway in ASC. We show here that the direction of change in spine density was mostly correlated to the upstream positive or negative regulation of the mTOR pathway and most rodent models of mutant mTOR regulators show increases in immature spines, based on morphological analyses. We further explore the idea that these mutations in these genes result in aberrant social behavior in rodent models that is due to these altered spine dynamics. This review should therefore pave the way for further research on the specific genes outlined, their effect on spine morphology or density with an emphasis on understanding the functional role of these changes in ASC.

Causal association between mTOR-dependent circulating protein levels and autism spectrum disorder: a Mendelian randomization study

“…ASD is a common neurological feature of these diseases which are all caused by mutations in genes upstream of mTORC1 (e.g., TSC1 and TSC2 in TSC [46], FMR1 in FXS [47], PTEN in PTEN hamartoma tumor syndrome [48] and NF1 in NF1 [49]). On the other hand, the mTOR signaling pathway participates in a number of pathological processes in patients with ASD, such as increased brain volume [50], increased dendritic spine density [51] and disrupted synaptic pruning [52].…”

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

“…Microcephaly, macrocephaly, enlarged brain size, increased cell density, decreased number of Purkinje cells in the cerebellum, cortical dysgenesis, and migration abnormalities have been observed in the brains of autistic individuals [ 66 ]. A disruption in synaptic pruning has also been detected in ASD [ 67 ]. The increased spine density in ASD brains has been correlated with increased phosphorylation of the mTOR as well as its downstream effectors, ribosomal protein S6 [ 68 ].…”

Gene × environment interactions in autism spectrum disorders

“…SHANK3 functions to interact with neuroligin and neurexin complexes to regulate activity-dependent synaptogenesis (Craig & Kang, 2007;Stamou et al, 2013). ERK, PI3K and mTOR signaling pathways are also strongly implicated in autism (Chaudry & Vasudevan, 2022;Lutz et al, 2021) and are important in regulating dendritic growth and synaptogenesis (Levitt & Campbell, 2009).…”

“…Connectivity is influenced by not only the structural complexity of dendrites, but also by spine density (Chaudry & Vasudevan, 2022;Nanou & Catterall, 2018). In cultured primary rat hippocampal neurons and brain slices, PCB 95 significantly increased dendritic spine formation via RyR signaling and CREB-dependent upregulation of miR132 (Lesiak et al, 2014).…”