Enterría-Morales, DanielLópez-González del Rey, NataliaBlesa, JavierLópez-López, IvetteGallet, SarahPrévot, VincentLópez-Barneo, Joséd'Anglemont de Tassigny, Xavier2022-07-112022-07-112020-07-15Enterría-Morales D, López-González del Rey N, Blesa J, López-López I, Gallet S, Prévot V, et al. Molecular targets for endogenous glial cell line-derived neurotrophic factor modulation in striatal parvalbumin interneurons. Brain Commun. 2020 Aug 27;2(2):fcaa105http://hdl.handle.net/10668/3776Administration of recombinant glial cell line-derived neurotrophic factor into the putamen has been tested in preclinical and clinical studies to evaluate its neuroprotective effects on the progressive dopaminergic neuronal degeneration that characterizes Parkinson's disease. However, intracerebral glial cell line-derived neurotrophic factor infusion is a challenging therapeutic strategy, with numerous potential technical and medical limitations. Most of these limitations could be avoided if the production of endogenous glial cell line-derived neurotrophic factor could be increased. Glial cell line-derived neurotrophic factor is naturally produced in the striatum from where it exerts a trophic action on the nigrostriatal dopaminergic pathway. Most of striatal glial cell line-derived neurotrophic factor is synthesized by a subset of GABAergic interneurons characterized by the expression of parvalbumin. We sought to identify molecular targets specific to those neurons and which are putatively associated with glial cell line-derived neurotrophic factor synthesis. To this end, the transcriptomic differences between glial cell line-derived neurotrophic factor-positive parvalbumin neurons in the striatum and parvalbumin neurons located in the nearby cortex, which do not express glial cell line-derived neurotrophic factor, were analysed. Using mouse reporter models, we have defined the genomic signature of striatal parvalbumin interneurons obtained by fluorescence-activated cell sorting followed by microarray comparison. Short-listed genes were validated by additional histological and molecular analyses. These genes code for membrane receptors (Kit, Gpr83, Tacr1, Tacr3, Mc3r), cytosolic proteins (Pde3a, Crabp1, Rarres2, Moxd1) and a transcription factor (Lhx8). We also found the proto-oncogene cKit to be highly specific of parvalbumin interneurons in the non-human primate striatum, thus highlighting a conserved expression between species and suggesting that specific genes identified in mouse parvalbumin neurons could be putative targets in the human brain. Pharmacological stimulation of four G-protein-coupled receptors enriched in the striatal parvalbumin interneurons inhibited Gdnf expression presumably by decreasing cyclic adenosine monophosphate formation. Additional experiments with pharmacological modulators of adenylyl cyclase and protein kinase A indicated that this pathway is a relevant intracellular route to induce Gdnf gene activation. This preclinical study is an important step in the ongoing development of a specific pro-endo-glial cell line-derived neurotrophic factor pharmacological strategy to treat Parkinson's disease.enAtribución-NoComercial 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc/4.0/Parkinson’s diseasePro-endo-GDNF pharmacologyParvalbumin interneuronsStriatumGene expressionEnfermedad de ParkinsonFactor neurotrófico derivado de la línea celular glialParvalbúminasCuerpo estriadoExpresión GénicaMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene ExpressionMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain::Prosencephalon::Telencephalon::Cerebrum::Basal Ganglia::Corpus StriatumMedical Subject Headings::Diseases::Nervous System Diseases::Neurodegenerative Diseases::Parkinson DiseaseMedical Subject Headings::Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Nerve Growth Factors::Glial Cell Line-Derived Neurotrophic Factors::Glial Cell Line-Derived Neurotrophic FactorMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Albumins::ParvalbuminsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Central Nervous System Agents::Neuroprotective AgentsMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain::Prosencephalon::Telencephalon::Cerebrum::Basal Ganglia::Corpus Striatum::Neostriatum::PutamenMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression::Transcription, Genetic::TranscriptomeMedical Subject Headings::Anatomy::Nervous System::NeuronsMedical Subject Headings::Anatomy::Nervous System::Neurons::InterneuronsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factorsresearch article32954345open access10.1093/braincomms/fcaa1052632-1297PMC7472905