Sonic Hedgehog Maintains Cellular and Neurochemical Homeostasis in the Adult Nigrostriatal Circuit

Abstract

SUMMARY Non cell-autonomous processes are thought to play critical roles in the cellular maintenance of the healthy and diseased brain but mechanistic details remain unclear. We report that the interruption of a non-cell autonomous mode of sonic hedgehog (Shh) signaling originating from dopaminergic neurons causes progressive, adult-onset degeneration of dopaminergic, cholinergic, and fast spiking GABAergic neurons of the mesostriatal circuit, imbalance of cholinergic and dopaminergic neurotransmission, and motor deficits reminiscent of Parkinson’s disease. Variable Shh signaling results in graded inhibition of muscarinic auto-receptor- and GDNF- expression in the striatum. Reciprocally, graded signals that emanate from striatal cholinergic neurons and engage the canonical GDNF receptor Ret inhibit Shh expression in dopaminergic neurons. Thus, we discovered a novel mechanism for neuronal subtype specific and reciprocal communication that is essential for neurochemical and structural homeostasis in the nigrostriatal circuit. These results provide integrative insights into non cell-autonomous processes likely at play in neurodegenerative conditions such as Parkinson’s disease.

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

“…However, as time advanced, we found a significant decrease of around 50% in the striatal Smo levels (4‐month‐old mice), and this reduction was further confirmed at 10 months of age (Supporting Information Figure S1d). Notably, Smo is not only expressed within the striatum by ACh and FS but also by other neuronal and non‐neuronal cells (Gonzalez‐Reyes et al, 2012) that do not undergo recombination in our model, strongly suggesting that the reduction in Smo mRNA levels observed in the interneurons of both ChAT‐Smo and PV‐Smo mice was likely underestimated. To study the deletion of Smo in both Cre lines at single cell level, we performed double in situ hybridization (ISH) combining Chat (Figure 2b) or Pvalb (Figure 2f) with Smo probes.…”

“…Previous studies suggested that Shh produced by DA SNpc is required for the maintenance of both striatal ACh and FS (Gonzalez‐Reyes et al, 2012). However, no alterations in the number of striatal interneurons have been associated with the progressive neurodegeneration of DA SNpc observed in Parkinson's disease (Fahn, 2009; Lang & Lozano, 1998).…”

“…Removal of Shh produced by DA SNpc during development has a profound effect on the number and function of adult striatal ACh and FS (Gonzalez‐Reyes et al, 2012). To separately investigate the effect of a postnatal reduction in the Shh signaling on ACh or FS, we independently decreased Smo expression in each cell type.…”

“…Simultaneous degeneration of striatal ACh and FS is correlated with the death of the DA SNpc, which is attributed to a decrease in striatal GDNF production (Gonzalez‐Reyes et al, 2012). To estimate whether a postnatal reduction in the number of striatal ACh was correlated with the neurodegeneration of the DA SNpc in the absence of FS neurodegeneration, we estimated the number of tyrosine hydroxylase (TH) immunoreactive DA SNpc in ChAT‐Smo mice (Figure 2a).…”

“…However, the role of GDNF in adult SNpc survival is still controversial (Kopra et al, 2015; Pascual & López‐Barneo, 2015) and needs further clarification. Concomitantly, Sonic hedgehog (Shh), an extracellular ligand involved in cellular specification during development (Ingham & McMahon, 2001), is produced by DA SNpc and is required during late embryogenesis and early postnatal life for the survival and phenotypic maintenance of FS and ACh as well as DA SNpc itself in a non‐cell‐autonomous manner (Gonzalez‐Reyes et al, 2012). However, no defect on striatal interneurons has been associated with the strong DA SNpc degeneration observed in Parkinson's disease, suggesting that further complexity is involved in postnatal neurotrophic maintenance of the striatal modulatory circuit.…”