Abstract
Theoretical and experimental work has demonstrated that excitatory (E) and inhibitory (I) currents within cortical circuits stabilize to a balanced state. This E/I balance, observed from single neuron to network levels, has a fundamental role in proper brain function and its impairment has been linked to numerous brain disorders. Over recent years, large amount of microarray and RNA-Sequencing datasets have been collected, however few studies have made use of these resources for exploring the balance of global gene expression levels between excitatory AMPA receptors (AMPARs) and inhibitory GABAA receptors. Here, we analyzed the relative relationships between these receptors to generate a basic transcriptional marker of E/I ratio. Using publicly available data from the Allen Brain Institute, we generated whole brain and regional signatures of AMPAR subunit gene expression in healthy human brains as well as the transcriptional E/I (tE/I) ratio. Then we refined the tE/I ratio to cell-type signatures in the mouse brain using data from the Gene Expression Omnibus. Lastly, we applied our workflow to developmental data from the Allen Brain Institute and revealed spatially and temporally controlled changes in the tE/I ratio during the embryonic and early postnatal stages that ultimately lead to the tE/I balance in adults.
Highlights
Theoretical and experimental work has shown that fast excitatory (E) and inhibitory (I) currents within cortical circuits stabilize rapidly to a balanced state[1,2,3,4,5,6]
GRIA2 was the most expressed AMPA receptors (AMPARs) subunit in the whole brain followed by GRIA4, GRIA1 and GRIA3 (Fig. 1b)
The strength of these clusters was examined through non-parametric bootstrap resampling to calculate both the approximately unbiased probability (AU) and bootstrap probability (BP) p values (Supplementary Fig. S3)
Summary
Theoretical and experimental work has shown that fast excitatory (E) and inhibitory (I) currents within cortical circuits stabilize rapidly to a balanced state[1,2,3,4,5,6]. The electrophysiological E/I (eE/I) balance is driven mainly by the concerted activity of excitatory α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and inhibitory γ-aminobutyric acid type A receptors (GABAARs)[15]; it remains unknown to what extent the transcription levels of each receptor are balanced across brain regions and developmental stages This information would prove highly important and useful since direct measurement of the activity of neurotransmitter receptors at the single neuron level in healthy humans is not currently possible with available technology. Substructure CA4 Dentate Gyrus CA1 Reticular nucleus (https://aging.brain-map.org/), which included a much higher number of individuals (n = 50), but was limited to only four regions: the hippocampus (HIP), temporal cortex (TCx), parietal cortex (PCx), and forebrain white matter (FWM) Together, these complementary analyses created a signature of AMPAR subunit expression in the healthy human brain. To investigate the usefulness of these signatures, we applied our method to single cell data from phenotypically characterized interneurons in mice and to RNA-sequencing data from the Allen Brainspan study that ranged from early embryonic stages to adulthood in humans
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