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R. Hamilton, M. H. Wang, J. E. Johnson, Jr., W. Xiao, L. J. Frishman, D. A. Fox; Retinal GABA Transporters Limit the Scotopic Electroretinogram (ERG) B-Wave Amplitude Increases in Mice with Gestational Lead Exposure (GLE). Invest. Ophthalmol. Vis. Sci. 2010;51(13):5588.
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© ARVO (1962-2015); The Authors (2016-present)
Low-level GLE produces scotopic ERG supernormality in children and adult rats characterized by increased a- and b-wave amplitudes. However, in adult mice with GLE the scotopic ERG b-wave increases marginally and inconsistently. An intravitreal injection of GABA that significantly increased b-wave amplitude in control mice did not produce supernormal b-waves in GLE mice (ARVO 2009), which suggested GABA-related retinal alterations in GLE mice. Our goals were to investigate the gene expression level, cellular localization and protein expression level of the GABA transporters and catabolic enzyme GABA transaminase (GABA-T) in control and GLE retinas, and to compare the ERG effects following GABA-T inhibition.
C57BL/6 female mice were exposed to 55 ppm lead throughout gestation and until postnatal day 10 (PN10): equivalent to the human gestation period. At PN60-75, control and GLE offspring and their retinas were studied. RT-qPCR analyzed gene expression. Confocal studies used fixed-frozen vertical sections followed by stereological analysis. Scotopic ERGs were assessed two weeks before, and 16 hours after a subcutaneous injection gabaculine: a suicide inhibitor of GABA-T.
GLE selectively increased gene expression of the murine plasmalemmal GABA transporters (Gat1, Gat3 and Gat4), vesicular GABA transporter (vGAT), and GABA-T. Confocal studies revealed that GLE, relative to controls, selectively increased the number of rods and bipolar cells as observed in adult GLE rats; expression of GAT4 in Müller glial cells; vGAT in horizontal cell dendrites; and GABA-T in retinal mitochondria. Gabaculine minimized the nSTR and enhanced the pSTR in control and GLE mice, but had no effect on ERG b-wave maximum amplitudes in either group.
GLE in mice increases the gene and corresponding protein expression of the GABA plasmalemmal and vesicular transporters and GABA-T. The up-regulation of the high-affinity Müller glial cell plasmalemmal GABA transporters in the retinas of GLE likely limits the scotopic ERG b-wave supernormality, with or without GABA, by rapidly reducing the [GABA] at critical outer and inner retinal sites that regulate ERG responses. The low-affinity GABA-T plays a critical role for sensitive inner retinal responses, but a minimal role in regulating the scotopic ERG b-wave maximum amplitude. Together, these results suggest that differences in retinal GABAergic and/or dopaminergic signaling might underlie the dissimilar ERG results in GLE rats and mice.
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