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Abstract
Gamma-aminobutyric acid (GABA), a major inhibitory transmitter in the central nervous system, is synthesized via either of two enzyme isoforms, GAD65 or GAD67. GAD65 is synthesized in the soma but functions at synaptic terminals in an activity-dependent manner, playing a distinct role in excitatory-inhibitory balance. However, the extent to which each GABAergic subtype expresses GAD65 in the resting state remains unclear. In this study, we compared GAD65 expression among six GABAergic subtypes: NPY+, nNOS+, PV+, SOM+, CR+, and CCK+. According to the results, the GABAergic subtypes were classified into two groups per region based on GAD65 expression levels: high-expression (NPY+ and nNOS+) and low-expression groups (PV+, SOM+, CR+, and CCK+) in the cerebral cortex and high-expression (NPY+, nNOS+, and CCK+) and low-expression groups (PV+, SOM+, and CR+) in the hippocampus. Moreover, these expression patterns revealed a distinct laminar distribution in the cerebral cortex and hippocampus. To investigate the extent of GAD65 transport from the soma to synaptic terminals, we examined GAD65 expression in colchicine-treated rats in which GAD65 was synthesized in the soma but not transported to terminals. We found a significant positive correlation in GAD65 expression across subtypes between colchicine-treated and control rats. In summary, each GABAergic subtype exhibits a distinct GAD65 expression pattern across layers of the cerebral cortex and hippocampus. In addition, the level of GAD65 expression in the soma can be used as a proxy for the amount of GAD65 in the cytoplasm. These findings suggest that exploration of the distinct profiles of GAD65 expression among GABAergic subtypes could clarify the roles that GABAergic subtypes play in maintaining the excitatory-inhibitory balance.
Highlights
The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is widely distributed in the central nervous system and is synthesized from glutamate via two isoforms of glutamic acid decarboxylase (GAD): GAD67 and GAD65
White squares indicate the regions enlarged in the panels on the right, and arrowheads indicate somata
We compared GAD65 expression among six GABAergic subtypes and found that GABAergic subtypes fell into two classes for each brain region from statistical analysis: a high-expression group (NPY+ and nNOS+ ) and a lowexpression group (PV+, SOM+, CR+, and CCK+ ) in the cerebral cortex, and a high-expression group (CCK+, NPY+, and nNOS+ ), and a low-expression group
Summary
The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is widely distributed in the central nervous system and is synthesized from glutamate via two isoforms of glutamic acid decarboxylase (GAD): GAD67 and GAD65. Repeated electrical stimulation has been shown to increase GABA contents and its release (Bowdler et al, 1983) while increasing GAD65 expression (Jinno and Kosaka, 2009) These previous data suggest that GAD65 expression is closely related to activity-dependent and phasic GABA synthesis. Elucidating the relationship between GABAergic subtypes and GAD65 expression would clarify the roles of GABAergic subtypes in activity-dependent and phasic inhibition under pathological conditions such as epileptic seizures and mental disorders To achieve this purpose, we compared GAD65 expression among several subtypes of neurons in the cerebral cortex and hippocampus under normal conditions. Neurons, neuropeptide Y-positive (NPY+ ) neurons, and neuronal nitric oxide synthase-positive (nNOS+ ) neurons This classification system was shared between the cerebral cortex and hippocampus. GAD65 expression in the soma of different subtypes was significantly and positively correlated between colchicine-treated and control rats
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