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 (PVϩ) interneurons, which only represent ϳ0.7% of all striatal neurons. The remaining 5% of GDNFϩ cells are cholinergic and somatostatinϩ interneurons. Surprisingly, medium spiny projection neurons (MSNs), the vast majority of striatal neurons that receive a strong DA innervation, do not express GDNF. PVϩ interneurons constitute an oscillatory functional ensemble of electrically connected cells that control MSNs' firing. Production of GDNF in the PVϩ neurons might be advantageous to supply synchronous activity-dependent release of GDNF in broad areas of the striatum. Stimulation of the GDNF-producing striatal PVϩ ensemble in PD patients could have therapeutic effects.

Substantia nigra dopaminergic neurons and striatal interneurons are engaged in three parallel but interdependent postnatal neurotrophic circuits

“…Those results are in agreement with our previous observation that FS are the main striatal GDNF producers with only a marginal contribution by ACh (Hidalgo‐Figueroa et al, 2012). …”

“…To test whether GDNF contributes to the degeneration of DA SNpc observed in the absence of Shh signaling in ChAT‐Smo mice, we estimated striatal Gdnf mRNA by qRT–PCR. As shown in Figure 5b, the levels of Gdnf were not decreased but increased at 4 months of age and a trend to increase was also observed at 10 months of age, a compensatory phenomenon that has been observed in other models of DA SNpc injury (Hidalgo‐Figueroa et al, 2012). To further confirm that the neurodegeneration of the DA SNpc did not involve GDNF alteration, we estimated its protein levels in 18‐month‐old mice.…”

“…Although FS are the main producers of striatal GDNF, ACh marginally contribute to its expression (Hidalgo‐Figueroa et al, 2012). To test whether GDNF contributes to the degeneration of DA SNpc observed in the absence of Shh signaling in ChAT‐Smo mice, we estimated striatal Gdnf mRNA by qRT–PCR.…”

“…We define three parallel and interdependent neurotrophic relationships characterized by (a) a bidirectional relation between DA SNpc and FS which may involve GDNF (Hidalgo‐Figueroa et al, 2012; Kopra et al, 2015; Pascual & López‐Barneo, 2015; Pascual et al, 2008); (b) a unidirectional relation between ACh and DA SNpc that does not involve GDNF; and (c) a dependence of ACh survival on Shh that not exclusively requires the DA SNpc but may imply FS and ACh (Figure 5d).…”

“…Modulatory striatal interneurons are engaged in reciprocal neurotrophic relationships with DA SNpc (Figure 1a). Adult FS and some striatal ACh produce glial cell line‐derived neurotrophic factor (GDNF; Hidalgo‐Figueroa, Bonilla, Gutiérrez, Pascual, & López‐Barneo, 2012), a potent dopaminotrophic factor required for survival and functionality of DA SNpc (Ibáñez & Andressoo, 2016; Kumar et al, 2015; Pascual et al, 2008). However, the role of GDNF in adult SNpc survival is still controversial (Kopra et al, 2015; Pascual & López‐Barneo, 2015) and needs further clarification.…”