The vulnerability of striatal projection neurons and interneurons to excitotoxicity is differentially regulated by dopamine during development.

Abstract The maturation of striatal projection neurons and interneurons is influenced by the development and integrity of their connectivity. In the present work, we have analyzed the modulation of striatum vulnerability to quinolinate (QUIN)-induced excitotoxicity in different neuronal populations by the nigrostriatal dopaminergic pathway during postnatal development. A single striatal lesion with 6-hydroxydopamine (6-OHDA) at the second postnatal day (P) 2 or QUIN at P7 induced a reduction in the striatal volume at P30, whereas an additive effect was observed when these two lesions were performed in the same animal. The analysis of different striatal neuronal populations showed that the excitotoxic lesion induced by QUIN over projection neurons stained with calbindin was partially reverted by the previous injection of 6-OHDA at P2. However, cholinergic interneurons were affected neither by the lack of dopamine innervation nor by QUIN treatment. This neuronal population also remained intact after the double lesion. In contrast, the number of other type of striatal interneurons, parvalbumin-positive neurons, were reduced by the dopaminergic ablation and also by the QUIN-induced excitotoxicity and this effect was additive after the double lesion when it was measured at P30. On the other hand, we studied the effect on the striatal outputs measuring the density of substance P-positive fibers in the substantia nigra and enkephalin-positive fibers in the globus pallidus. A reduction in substance P-positive fibers was observed in 6-OHDA injected animals, while the density of enkephalin-positive fibers was only decreased after QUIN treatment. The double lesion did not modify the effects of the single lesions. In conclusion, our results show that dopamine modulates the vulnerability to excitotoxicity during striatal postnatal development, and this effect is specific for projection neurons. Furthermore, striatonigral and striatopallidal pathways are differentially regulated by the activation of dopamine or glutamate receptors.