title: GDNF is predominantly expressed in the PV+ neostriatal interneuronal ensemble in normal mouse and after injury of the nigrostriatal pathway.
abstract: 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. GDNF mRNA expression 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 remaining 5% 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 of GDNF in broad areas of the striatum. Stimulation of the GDNF-producing striatal PV+ ensemble in PD patients could have therapeutic effects.
authors.affiliation: Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 41013 Sevilla, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Hidalgo-Figueroa
authors.forename: Sonia
authors.initials: S
authors.lastname: Bonilla
authors.forename: Francisco
authors.initials: F
authors.lastname: Gutiérrez
authors.forename: Alberto
authors.initials: A
authors.lastname: Pascual
authors.forename: José
authors.initials: J
authors.lastname: López-Barneo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D017072:Neostriatum / Q000166:cytology* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D013997:Time Factors
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; C497929:Ppp1r1b protein, mouse; D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D002795:Choline O-Acetyltransferase