Molecular targets for endogenous glial cell line-derived neurotrophic factor modulation in striatal parvalbumin interneurons

Abstract

Administration of recombinant glial cell line-derived neurotrophic factor (GDNF) into the putamen has been tested in preclinical and clinical studies to evaluate its neuroprotective effects on the progressive dopaminergic neuronal degeneration that characterises Parkinson’s disease. However, intracerebral GDNF 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 GDNF could be increased. GDNF is naturally produced in the striatum from where it exerts a trophic action on the nigrostriatal dopaminergic pathway. Most of striatal GDNF is synthesized by a subset of GABAergic interneurons characterised by the expression of parvalbumin. We sought to identify molecular targets specific to those neurons and which are putatively associated with GDNF synthesis. To this end, the transcriptomic differences between GDNF-positive parvalbumin neurons in the striatum and parvalbumin neurons located in the nearby cortex, which do not express GDNF, 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 nonhuman 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-GDNF pharmacological strategy to treat Parkinson’s disease.

Evolutionarily conservative and non-conservative regulatory networks during primate interneuron development revealed by single-cell RNA and ATAC sequencing

“…In MGE, we identified a small group of cells specifically expressing CRABP1 and ANGPT2 . Combined with the scRNA-seq analysis of PV + interneurons and the developmental process of GE in mice, 17 , 98 , 99 those cells were defined as the PV + interneuron precursors derived from MGE.…”

Mouse Embryonic Stem Cells Expressing GDNF Show Enhanced Dopaminergic Differentiation and Promote Behavioral Recovery After Grafting in Parkinsonian Rats

“…We assessed the proportion of Calbindin- and GIRK2-positive cells and found significant increases in both dopaminergic cell types. As previously reported, GDNF can provide survival signals to different niches of neurons such as sympathetic, enteric, motor, and other catecholaminergic neurons such as noradrenergic ( Lin et al, 1993 ; Coulpier and Ibáñez, 2004 ; Pascual et al, 2008 ; Cortés et al, 2016 ; Ito and Enomoto, 2016 ; Enterría-Morales et al, 2020b , a ). Interestingly, the proportion of differentiated serotonin neurons was unchanged in GDNF-ESC.…”

PEN Receptor GPR83 in Anxiety-Like Behaviors: Differential Regulation in Global vs Amygdalar Knockdown

“…In contrast to the amygdala, we have recently reported that GPR83 is primarily expressed in cholinergic interneurons in the NAc ( Fakira et al, 2019 ). However, a small percentage of neurons were not characterized but recent studies demonstrated that PV + neurons in the striatum indeed express GPR83 ( Enterría-Morales et al, 2020 ). Because PV + neurons in the NAc have been specifically implicated in anxiety-like approach behaviors, we also characterized PV + and GPR83 + co-expression in the NAc.…”