Cell Type-Specific Gene Expression of Alpha 5 Subunit-Containing Gamma-Aminobutyric Acid Subtype A Receptors in Human and Mouse Frontal Cortex

Abstract

Converging evidence suggests that deficits in somatostatin (SST)-expressing neuron signaling contributes to major depressive disorder. Preclinical studies show that enhancing this signaling, specifically at α5 subunit-containing γ-ami­nobutyric acid subtype A receptors (α5-GABA_ARs), provides a potential means to overcome low SST neuron function. The cortical microcircuit comprises multiple subtypes of inhibitory γ-aminobutyric acid (GABA) neurons and excitatory pyramidal cells (PYCs). In this study, multilabel fluorescence in situ hybridization was used to characterize α5-GABA_AR gene expression in PYCs and three GABAergic neuron subgroups – vasoactive intestinal peptide (VIP)-, SST-, and parvalbumin (PV)-expressing cells – in the human and mouse frontal cortex. Across species, we found the majority of gene expression in PYCs (human: 39.7%; mouse: 54.14%), less abundant expression in PV neurons (human: 20%; mouse: 16.33%), and no expression in VIP neurons (0%). Only human SST cells expressed GABRA5, albeit at low levels (human: 8.3%; mouse: 0%). Together, this localization suggests potential roles for α5-GABA_ARs within the cortical microcircuit: (1) regulators of PYCs, (2) regulators of PV cell activity across species, and (3) sparse regulators of SST cell inhibition in humans. These results will advance our ability to predict the effects of pharmacological agents targeting α5-GABA_ARs, which have shown therapeutic potential in preclinical animal models.

Cellular and molecular signatures of in vivo GABAergic neurotransmission in the human brain

“…For instance, we observed that the spatial pattern of [ 11 C]Ro15-4513 binding covaried most strongly with a gene cluster containing GABRA5, GABRA2 and SST. This finding is consistent with preclinical literature showing that GABAARα5 are enriched on principal cell membranes targeted by SST cells (5,26,40). Moreover, [ 11 C]Ro15-4513 has been shown to present 10-15-fold higher affinity to human cloned GABAARα5 than to GABAARα1-3 (23) and the co-expression of GABRA2 and GABRA5 was previously shown by immunohistochemistry in the rat brain (16), which we observed in our analyses as well.…”

Neurobiology and Therapeutic Potential of α5-GABA Type A Receptors

“…In the cortex, pyramidal cells exhibit dendritically localized α5 GABA A Rs at sites innervated by bitufted interneurons (an SST positive neuron class; Ali and Thomson, 2008). A recent human and mouse prefrontal cortex gene expression study determined that the majority of α5 GABA A Rs are in pyramidal cells, followed by parvalbumin interneurons (Hu et al, 2018). Interestingly, α5 GABA A R mRNA was uniquely expressed in human SST interneurons, albeit at a low level.…”

Depressive-like behaviors induced by somatostatin-positive GABA neuron silencing are rescued by alpha 5 GABA-A receptor potentiation

“…GABA neurons shape this activity differently based on non-overlapping populations that co-express SST, the calcium-binding protein parvalbumin (PV+), or the ionotropic serotonin receptor 5HT3aR with or without vasoactive intestinal peptide (VIP+) (Rudy et al, 2011). SST+ cells gate excitatory PN input via dendritic inhibition and modulate output via perisomatic disinhibition through SST-PV+ cell afferents (Fee et al, 2017;Hu et al, 2019). Dendritic SST+ cell inhibition is partially mediated by GABA acting on GABA-A and GABA-B receptors (GABAA-R/GABAB-R) (Urban-Ciecko et al, 2015;Schulz et al, 2018), whereas the SST peptide is released under distinct firing conditions (Katona et al, 2014;Yavorska and Wehr, 2016).…”

“…The regional and functional differentiation of GABAA-Rs depend upon heteropentameric subunit composition, commonly containing two α, two β, and one γ-subunit (Rudolph et al, 2001;Sieghart and Sperk, 2002). SST+ cell functions are partially mediated by a5 subunit-containing-GABAA-Rs given their localization to PN dendrites and PV+ cells in the PFC, hippocampus (HPC), and ventral striatum (Ali and Thomson, 2008;Schulz et al, 2018;Hu et al, 2019). GABRA5 transcripts, encoding α5GABAA-Rs, were also reduced in the PFC of MDD and aged subjects (Oh et al, 2019).…”

“…or RNA labeling(Hu et al, 2019) may inform therapeutic strategies.In conclusion, we demonstrated that brain-wide SST+ cell function regulates mood and cognitive functions and found support that acute disruptions contributing to anxiety-and anhedonia-like behaviors, overall behavioral emotionality, and impaired memory may reflect similar processes in psychiatric diseases over a longer scale. Deficits arising from brain-wide low SST+ cell function were rescued by α5-PAM, representing a promising new avenue for the development of targeted antidepressants.…”