Age-related decreased inhibitory vs. excitatory gene expression in the adult autistic brain

Abstract

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impaired social interaction and communication, and restricted behavior and interests. A disruption in the balance of excitatory and inhibitory neurotransmission has been hypothesized to underlie these disorders. Here we demonstrate that genes of both pathways are affected by ASD, and that gene expression of inhibitory and excitatory genes is altered in the cerebral cortex of adult but not younger autistic individuals. We have developed a measure for the difference in the level of excitation and inhibition based on gene expression and observe that in this measure inhibition is decreased relative to excitation in adult ASD compared to control. This difference was undetectable in young autistic brains. Given that many psychiatric features of autism are already present at an early age, this suggests that the observed imbalance in gene expression is an aging phenomenon in ASD rather than its underlying cause.

Advancing the understanding of autism disease mechanisms through genetics

“…This further highlights how early developmental abnormalities may have repercussions later on. It is also important to note that E/I imbalance studies have mainly been carried out in animal models, hence a detailed evaluation of when, where and how an E/I shift contributes to the ASD phenotypes in humans is warranted 161–163 .…”

Elevated gene expression of most microglial markers, and reduced expression of most pyramidal neuron and interneuron markers, in postmortem autism cortex

“…Nevertheless, that study failed to find differences in expression of neuronal and glial marker genes in ASD, probably due to the few markers used. Although there is some overlap between the cell type marker genes used here and microglia activation genes 33 or neurotransmission genes 34 , we propose that the parsimonious interpretation of these results is that ASD brains contain alterations in cell density. We do so for the following reasons: (1) marker genes shift their expression together in the same direction in the ASD versus control comparison, rather than being driven by a minority subset as expected when only a specific pathway is altered, and (2) the median fold changes for transcripts encoding proteins localized in different neuronal compartments are all reduced, which is unexpected if only neuronal processes changed in their density.…”

“…Furthermore, the enrichment of synaptic marker genes in under-expressed modules in ASD 5 may be due to dysfunctional synaptic formation 9,10 . Indeed, gene markers related to neurotransmission are underexpressed in adult ASD post-mortem cortex 34 .…”

Dietary Restriction Affects Neuronal Response Property and GABA Synthesis in the Primary Visual Cortex

“…There are three critical differences that are worthy of attention in subsequent investigations: (1) Different species may display variations in neural plasticity. (2) Animals at different age may show different effects of DR on the inhibitory neurotransmitter systems because the excitation-inhibition balance may change with age [ 46 , 67 – 69 ]. (3) Different types, period and level of food restriction, such as short-term and long-term, may also lead to the difference of DR effects [ 70 ].…”