Interactions of neurotransmitter systems during postnatal development of the rat hippocampal formation: Effects of cisplatin

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Abstract

The distribution of neuroimmunohistochemical markers for the serotoninergic, noradrenergic, glutamatergic and GABAergic systems (respectively, 5HT2AR, β1AR, GluR 2/3 and GAD65/67) was determined in the hippocampal formation at stages PD11, PD17 and PD30 of postnatal development of untreated rats and cisplatin-treated rats after a single injection of the drug at 10 days of life. In the different time points the neurons of the dentate gyrus and Cornu Ammonis progressively acquire mature morphological characteristics, and cell genesis, migration of interneurons and differentiation of mossy cells occur.

Cisplatin induced decrease in immunoreactivity for most of the selected neurotransmitter markers, thereby altering the postnatal development of circuits in the hippocampal formation. Cisplatin also brought out clear evidence for an interaction between excitatory and inhibitory neurotransmitter markers during the postnatal maturation of cells and fiber projections containing GluR2/3 and GAD65, despite the fact that glutamatergic neurons and GABAergic interneurons are divergent in their source of genesis and in their mode of migration. In fact, GluR2/3 immunofluorescence was increased in the principal cells early, at PD11, possibly to reduce the calcium influx into the cell. Moreover, cisplatin might cause a loss of GABAergic interneurons early and reduction of fiber projections to hippocampal layers due to altered cell migration or to cell injury; late changes, particularly in GAD67 cell number in the dentate gyrus did not result in redistribution or recovery in treated rats. With the use of cisplatin it has been demonstrated here for the first time that the critical differentiation of dentate gyrus hilar β1AR and GluR2/3 mossy cells takes place between PD11 and PD17. Changes in neurotransmitter marker immunopositivity occurred subsequently to cytoarchitectural changes in the dentate gyrus and Cornu Ammonis which were already evident one day after cisplatin injection, suggesting that degeneration and cell loss may have occurred.

Cisplatin was found to be a useful tool for following CNS development and for understanding how hippocampal neuronal networks react to injury. Furthermore, cisplatin-induced neurotoxicity may be used to reveal useful information on the genesis, migration and distribution, and differentiation of distinct types of hippocampal neurons.

Highlights

▸ The chemotherapeutic cisplatin induces cytotoxic effects on CNS. ▸ We examine the changes in the developing CNS during rat postnatal life. ▸ A single injection of cisplatin impaired the hippocampus formation and maturation. ▸ The neurotransmitter patterns and morphology are damaged. ▸ Our model system suggests attention when cisplatin is given during childhood.

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