GDNF Is predominantly expressed in the PV+ neostriatal interneuronal ensemble in normal mouse and after Injury of the nigrostriatal pathway

Glial cell line-derived neurotrophic factor (GDNF) is absolutely required for survival of dopaminergic (DA) nigrostriatal neurons and protect them from toxic insults. Hence, it is a promising, albeit experimental, therapy for Parkinson’s disease (PD). However, the source of striatal GDNF is not well known. GDNF seems to be normally synthesized in neurons, but numerous reports suggest GDNF production in glial cells, particularly in the injured brain. We have studied in detail striatal GDNF production in normal mouse and after damage of DA neurons with MPTP. Striatal GDNF mRNA was present in neonates but markedly increased during the first 2–3 postnatal weeks. Cellular identification of GDNF by unequivocal histochemical methods demonstrated that in normal or injured adult animals GDNF is expressed by striatal neurons and is not synthesized in significant amounts by astrocytes or microglial cells.GDNFmRNAexpression was not higher in reactive astrocytes than in normal ones. Approximately 95% of identified neostriatal GDNF-expressing cells in normal and injured animals are parvalbumin-positive (PV_) interneurons, which only represent_0.7% of all striatal neurons. The remaining5%of GDNF_cells are cholinergic and somatostatin_interneurons. Surprisingly, medium spiny projection neurons (MSNs), the vast majority of striatal neurons that receive a strong DA innervation, do not express GDNF. PV_interneurons constitute an oscillatory functional ensemble of electrically connected cells that control MSNs’ firing. Production of GDNF in the PV_ neurons might be advantageous to supply synchronous activity-dependent release ofGDNFin broad areas of the striatum. Stimulation of the GDNF-producing striatalPV_ ensemble in PD patients could have therapeutic effects