Brain-Derived Neurotrophic Factor Modulates the Development of the Dopaminergic Network in the Rodent Retina

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Abstract
Dopaminergic cells in the retina express the receptor for brain-derived neurotrophic factor (BDNF) (Cellerino and Kohler, 1997). To investigate whether BDNF can influence the development of the retinal dopaminergic pathway, we performed intraocular injections of BDNF during the second or third postnatal week and visualized the dopaminergic system with tyrosine hydroxylase (TH) immunohistochemistry. Both regimens of BDNF treatment caused an increase in TH immunoreactivity in stratum 1 and stratum 3 of the inner plexiform layer (IPL). D2 dopamine receptor immunoreactivity, a presynaptic marker of dopaminergic cells (Veruki, 1996), was also increased in stratum 1 and stratum 3 of the inner plexiform layer. These data suggest that BDNF causes sprouting of dopaminergic fibers in the inner plexiform layer. Other neurochemical systems, for example, the cholinergic amacrine cells, remained unaffected. Similar effects were observed after injections of neurotrophin-3 and neurotrophin-4, but not nerve growth factor. Analysis of whole-mounted TH-immunolabeled retinae revealed hypertrophy of dopaminergic cells (+41% in soma areas;p< 0.01) and an increase of labeled dopaminergic varicosities in stratum 1 of the IPL (+51%;p< 0.01) after BDNF treatment. The opposite was observed in mice homozygous for a null mutation of thebdnfgene: dopaminergic cells were atrophic (−22.5% in soma areas;p< 0.05), and the density of TH-positive varicosities in stratum 1 was reduced (57%;p< 0.01). We conclude that BDNF controls the development of the retinal dopaminergic network and may be particularly important in determining the density of dopaminergic innervation in the retina.