The effect of age and sex on the expression of GABA signaling components in the human hippocampus and entorhinal cortex

Abstract

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the nervous system. The GABA signaling system in the brain is comprised of GABA synthesizing enzymes, transporters, GABAA and GABAB receptors (GABAAR and GABABR). Alterations in the expression of these signaling components have been observed in several brain regions throughout aging and between sexes in various animal models. The hippocampus is the memory centre of the brain and is impaired in several age-related disorders. It is composed of two main regions: the Cornu Ammonis (CA1-4) and the Dentate Gyrus (DG), which are interconnected with the Entorhinal Cortex (ECx). The age- and sex-specific changes of GABA signaling components in these regions of the human brain have not been examined. This study is the first to determine the effect of age and sex on the expression of GABA signaling components-GABAAR α1,2,3,5, β1-3, γ2, GABABR R1 and R2 subunits and the GABA synthesizing enzymes GAD 65/67-in the ECx, and the CA1 and DG regions of the human hippocampus using Western blotting. No significant differences were found in GABAAR α1,2,3,5, β1-3, γ2, GABABR R1 and R2 subunit and GAD65/76 expression levels in the ECx, CA1 and DG regions between the younger and older age groups for both sexes. However, we observed a significant negative correlation between age and GABAAR α1subunit level in the CA1 region for females; significant negative correlation between age and GABAAR β1, β3 and γ2 subunit expression in the DG region for males. In females a significant positive correlation was found between age and GABAAR γ2 subunit expression in the ECx and GABABR R2 subunit expression in the CA1 region. The results indicate that age and sex do not affect the expression of GAD 65/67. In conclusion, our results show age- and sex-related GABAA/BR subunit alterations in the ECx and hippocampus that might significantly influence GABAergic neurotransmission and underlie disease susceptibility and progression.

Age, Education Years, and Biochemical Factors Are Associated with Selective Neuronal Changes in the Elderly Hippocampus

“…Similarly, no age-related alterations in GAT1 protein levels were observed in the sensory, motor, temporal, and cerebellar cortical areas of human brains [ 36 ]. The expression of multiple components of the GABAergic system, but not GATs, was previously quantified by Western blotting in the human hippocampus and entorhinal cortex during aging [ 37 ]. No changes in older groups were found for GAD65/67 enzymes and for the majority of the GABA receptor subunits [ 37 ].…”

“…It has been previously shown how aging affects the expression of multiple GABAergic markers in the human cerebral cortex, including GAD isoforms and GAT1 [ 36 ]. This topic was also investigated in the human hippocampus, but data regarding GAT1 expression is still unavailable [ 37 ].…”

The GABAergic System and Endocannabinoids in Epilepsy and Seizures: What Can We Expect from Plant Oils?

“…The activities of these transporters determine the amount of available GABA for activation by presynaptic nerve terminals and glial cells. Disruption of these factors contributes to altered GABAergic transmission in epilepsy [ 22 , 26 , 36 ]. A large number of pro-convulsant drugs impair the inhibition mediated by GABA.…”

“…A large number of pro-convulsant drugs impair the inhibition mediated by GABA. Glutamic acid decarboxylase (GAD) is diminished in interneurons in discrete regions of the epileptogenic cortex and hippocampus, and high levels of the antibody-GAD are convulsants and produce cerebellar ataxia and temporal lobe epilepsy [ 26 , 36 , 37 ].…”

Crosstalk Between GABAergic Neurotransmission and Inflammatory Cascades in the Post-ischemic Brain: Relevance for Stroke Recovery

“…On the other hand, quantitative studies on human cortical samples revealed that the expression of most of the elements comprising the GABAergic system remains robust throughout age with the exception of certain subunits and GAT-1 (Pandya et al, 2019 ). Additionally, alterations in subunit expression differ throughout aging between males and females (Ethiraj et al, 2021 ).…”