Effect of embryonic knock-down of GABAA receptors on the levels of monoamines and their metabolites in the CNS of the mouse

In vitro evidence indicates that gamma-aminobutyric acid (GABA), acting at GABA(A) receptors, exerts a positive trophic effect on monoaminergic neurons during embryogenesis. To determine whether in vivo antagonism of GABA(A) receptors during embryogenesis interferes with the development of monoaminergic neurons, we used mice in which the number of GABA(A) receptors was decreased by 50% by targeted deletion of the beta(3) subunit gene of the GABA(A) receptor. Levels of serotonin, dopamine, norepinephrine, and the metabolites 3,4-deoxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid were measured in the brainstem, cortex, striatum and spinal cord of female adult homozygous null (beta3-/-) and wild-type (beta3+/+) mice, as well as progenitor C57BL/6J and Strain 129/SvJ mice. The level of norepinephrine in the spinal cord of beta3-/- mice was 44% less than that of beta3+/+ mice, and did not differ in the brainstem, cortex or striatum. This finding suggests that beta3 subunit-containing GABA(A) receptors mediate the trophic effects of GABA on a subpopulation of spinally-projecting noradrenergic neurons. In contrast, the levels of serotonin, dopamine or their metabolites were unaffected, suggesting that the development of serotonergic and dopaminergic neurons may require activation of only a small fraction of GABA(A) receptors or may not be dependent on beta3 subunit-containing GABA(A) receptors. Finally, Strain 129/SvJ and C57BL/6J mice differed with respect to the levels of dopamine and its metabolites in the brainstem, spinal cord and cortex. These differences may need to be considered when assessing the phenotype of gene-targeted mice for which these mice serve as progenitor strains.