Abstract
GABA type-A receptors are essential for fast inhibitory neurotransmission and are critical in brain function. Surprisingly, expression of receptor subunits is highly variable among individuals, but the cause and impact of this fluctuation remains unknown. We have studied sources of variation for all 19 receptor subunits using massive expression data sets collected across multiple brain regions and platforms in mice and humans. Expression of Gabra1, Gabra2, Gabrb2, Gabrb3, and Gabrg2 is highly variable and heritable among the large cohort of BXD strains derived from crosses of fully sequenced parents—C57BL/6J and DBA/2J. Genetic control of these subunits is complex and highly dependent on tissue and mRNA region. Remarkably, this high variation is generally not linked to phenotypic differences. The single exception is Gabrb3, a locus that is linked to anxiety. We identified upstream genetic loci that influence subunit expression, including three unlinked regions of chromosome 5 that modulate the expression of nine subunits in hippocampus, and that are also associated with multiple phenotypes. Candidate genes within these loci include, Naaa, Nos1, and Zkscan1. We confirmed a high level of coexpression for subunits comprising the major channel—Gabra1, Gabrb2, and Gabrg2—and identified conserved members of this expression network in mice and humans. Gucy1a3, Gucy1b3, and Lis1 are novel and conserved associates of multiple subunits that are involved in inhibitory signaling. Finally, proximal and distal regions of the 3′ UTRs of single subunits have remarkably independent expression patterns in both species. However, corresponding regions of different subunits often show congruent genetic control and coexpression (proximal-to-proximal or distal-to-distal), even in the absence of sequence homology. Our findings identify novel sources of variation that modulate subunit expression and highlight the extraordinary capacity of biological networks to buffer 4–100 fold differences in mRNA levels.
Highlights
There is an extraordinarily high level of variation in expression of messenger RNAs of key inhibitory GABA type-A receptors (GABA(A)R) in human brain
Expression, variation, and heritability We examined expression of GABA(A)R subunits across six brain regions, two species, and multiple expression platforms using a large number of probes and probe sets, and RNA sequencing (RNA-seq)
We find that anxietyassociated phenotypes are associated with variants near Gabrb3 (LRS.12, B allele) on Chr 7 (GeneNetwork BXD Trait IDs: 11389, 11390, 11385, 11388) [9]
Summary
There is an extraordinarily high level of variation in expression of messenger RNAs of key inhibitory GABA type-A receptors (GABA(A)R) in human brain. This is a remarkable range that exceeds that which is often achieved in knock-in and knock-down experiments in genetically engineered lines of mice This variation in expression is doubly remarkable because dysregulation of GABA(A)R have been linked to a wide range of abnormalities and neurological diseases, including epilepsy, autism, impulsivity, substance abuse disorders, mood, psychiatric disease, and chronic pain. This raises an important question as to the causes and consequences of the high level of endogenous variation among normal humans. Is it a technical artifact of arraybased methods? Is it due to difficulties in obtaining high quality RNA from human brain? Or does it reflect flexible use of GABA(A)R subunits to assemble pentameric receptors?
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