Abstract
As neurotransmitter, GABA is fundamental for physiological processes in the developing retina. Its synthesis enzymes are present during retinal development, although the molecular regulatory mechanisms behind the changes in expression are not entirely understood. In this study, we revealed the expression patterns of glutamic acid decarboxylase 67(GAD67) and its coding gene (GAD1) and its potential miRNA-dependent regulation during the first three postnatal weeks in rat retina. To gain insight into the molecular mechanisms, miRNA-sequencing supported by RT-qPCR and in situ hybridization were carried out. GAD1 expression shows an increasing tendency, peaking at P15. From the in silico-predicted GAD1 targeting miRNAs, only miR-23 showed similar expression patterns, which is a known regulator of GAD1 expression. For further investigation, we made an in situ hybridization investigation where both GAD67 and miR-23 also showed lower expression before P7, with the intensity of expression gradually increasing until P21. Horizontal cells at P7, amacrine cells at P15 and P21, and some cells in the ganglion cell layer at several time points were double labelled with miR-23 and GAD67. Our results highlight the complexity of these regulatory networks and the possible role of miR-23 in the regulation of GABA synthesizing enzyme expression during postnatal retina development.
Highlights
GABA was discovered in the vertebrate brain in 1950, and later its function as an inhibitory neurotransmitter was proved in the central nervous system (CNS) [1,2,3]
GABA is synthetized from glutamate by two different isoforms of the glutamic acid decarboxylase (GAD) enzyme, which are distinguished by their molecular weights: GAD65 (~65 kDa) and GAD67 (~67 kDa) [12,13]
GAD65 knockout (GAD65−/−) mice showed normal GABA levels in the brain, while in another study, the GAD67 heterozygote (GAD67−/+) mice showed significantly lower levels of GABA, their GAD65 level was normal. These results indicate that GAD67 is essential for GABA synthesis in the brain [16,17]
Summary
GABA (gamma-aminobutyric acid) was discovered in the vertebrate brain in 1950, and later its function as an inhibitory neurotransmitter was proved in the central nervous system (CNS) [1,2,3]. It has an indispensable predominant role in the developing mammalian. The GAD65 isoform is usually localized in synaptic terminals, while GAD67 occurs throughout the cell, including dendrites and the soma [14,15]. Their differential participation in the GABA synthesis in the CNS has been the focus of numerous studies. These results indicate that GAD67 is essential for GABA synthesis in the brain [16,17]
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