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Shawntay Chaney, Shradha Mukherjee, Anand Giddabasappa, Jerry E. Johnson, Donald A. Fox; Spatiotemporal Development of Late-Born Rods and Bipolar Cells and Their Synapses in Mice with Gestational Lead Exposure. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3965.
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Gestational lead exposure (GLE) produces supernormal ERGs in children (Rothenberg et al., IOVS 2002) and increases and prolongs mouse retinal progenitor cell (RPC) proliferation during development. This results in a selective 25-30% increase in the number of rod photoreceptors and bipolar cells (BCs) in adult mice (Giddabasappa et al., EHP 2011). The current goal was to investigate the spatiotemporal development of late-born rods and BCs and their synapses in GLE retinas.
C57BL/6 female mice were exposed to water or lead throughout gestation (E) and until postnatal day 10 (PN10). Fixed-frozen vertical sections from E18.5-PN10 central retina were processed for confocal immunohistochemistry using well-characterized antibodies.
The spatiotemporal expression of OTX2-immunoreactivity (IR), a rod and BC transcription factor, was similar in control and GLE retinas, although the number of OTX2-IR cells significantly increased in GLE retinas. In GLE retinas the onset of rhodopsin-IR, but not recoverin-IR, was delayed 2-3 days. By PN3, the number of rhodopsin-IR and recoverin-IR rods significantly increased in GLE retinas. The number of Chx10-IR RPCs significantly increased in GLE retinas during early postnatal development. Chx10-IR localized to BCs at PN3 in controls and at PN5 in GLE retinas. At PN5, significantly more BCs were Chx10-IR in GLE than controls. In controls, protein-kinase C alpha (PKC)-IR was present in the proximal inner nuclear layer (INL) at PN5 and localized to rod BCs by PN7. In GLE retinas, PKC-IR in the proximal INL significantly increased at PN5, however, by PN7 PKC-IR was not yet completely localized to rod BCs. In control and GLE retinas, plasma membrane calcium ATPase (PMCA)-IR appeared in the outer plexiform layer (OPL) at PN5. Vesicular glutamate transporter 1 (VGluT1)-IR first labeled the OPL at PN5 in control and GLE, but significantly decreased in GLE through PN10. In controls, VGluT1 labeled inner plexiform layer (IPL) sublaminae a (IPLa) weakly at PN7, and IPLa and IPLb strongly at PN10. In GLE retinas, VGluT1 labeled IPLa minimally at PN7 and normally at PN10, and IPLb minimally at PN10.
GLE did not alter the onset of rod and BC cell fate (OTX2-IR) or cone (recoverin) differentiation. However, GLE delayed the onset of rod and BC differentiation (rhodopsin-, Chx10- and PKC-IR) and increased the number of these late-born neurons. GLE did not alter rod spherule development, assessed by PMCA-IR, although it delayed OPL and IPL synaptic VGluT1 expression. These delayed differentiation results are consistent with the increased and prolonged RPC proliferation in GLE retinas that underlie the increased rod and BC cellularity in adult mice.
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