Sex- and age-related changes in GABA signaling components in the human cortex

Madhavi Pandya,Richard L Faull,Henry J Waldvogel,Andrea Kwakowsky,Clinton Turner,Thulani H Palpagama

doi:10.1186/s13293-018-0214-6

Madhavi Pandya, Richard L Faull + Show 4 more

Open Access

https://doi.org/10.1186/s13293-018-0214-6

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Abstract

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the nervous system. Previous studies have shown fluctuations in expression levels of GABA signaling components—glutamic acid decarboxylase (GAD), GABA receptor (GABAR) subunit, and GABA transporter (GAT)—with increasing age and between sexes; however, this limited knowledge is highly based on animal models that produce inconsistent findings. This study is the first analysis of the age- and sex-specific changes of the GAD, GABAA/BR subunits, and GAT expression in the human primary sensory and motor cortices; superior (STG), middle (MTG), and inferior temporal gyrus (ITG); and cerebellum. Utilizing Western blotting, we found that the GABAergic system is relatively robust against sex and age-related differences in all brain regions examined. However, we observed several sex-dependent differences in GABAAR subunit expression in STG along with age-dependent GABAAR subunit and GAD level alteration. No significant age-related differences were found in α1, α2, α5, β3, and γ2 subunit expression in the STG. However, we found significantly higher GABAAR α3 subunit expression in the STG in young males compared to old males. We observed a significant sex-dependent difference in α1 subunit expression: males presenting significantly higher levels compared to women across all stages of life in STG. Older females showed significantly lower α2, α5, and β3 subunit expression compared to old males in the STG. These changes found in the STG might significantly influence GABAergic neurotransmission and lead to sex- and age-specific disease susceptibility and progression.

Highlights

GABAergic interneurons account for approximately 20% of cortical neurons in the human brain that modulate neuronal activity via Gamma-aminobutyric acid (GABA) based neuronal inhibition [1]
In this study, we report that the GABAergic system in the human primary sensory and motor cortices, cerebellum, and inferior temporal gyrus (ITG) and Middle temporal gyrus (MTG) is generally well protected against sex- and age-related alterations
The temporal lobes have a unique architecture and functional characteristics that make them vulnerable to certain disease processes. They are interconnected through the anterior commissure, the corpus callosum, and the hippocampal commissure, and these connections are among the underlying mechanisms that contribute to disease processes

Summary

Introduction

GABAergic interneurons account for approximately 20% of cortical neurons in the human brain that modulate neuronal activity via GABA based neuronal inhibition [1]. Previous studies have reported aging-related alterations in the levels of both GAD isoforms, GAD65 and GAD67, in different species and brain areas. Using magnetic resonance spectroscopy several studies have found a reduction in concentration of GABA levels with age in animal models, nonhuman primates, and humans [13,14,15]. Evidence suggesting loss of grey matter tissue fraction that causes an overall reduction in GABA concentrations confounds the correlation of age-related loss of GABA [16, 17]. The literature shows controversial (2019) 10:5 results and species differences in GAD expression, some studies demonstrating an increase rather than a decrease in GAD levels in prefrontal cortical areas [2, 18, 19]

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