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

Abstract

The striatum integrates motor behavior using a well‐defined microcircuit whose individual components are independently affected in several neurological diseases. The glial cell line‐derived neurotrophic factor (GDNF), synthesized by striatal interneurons, and Sonic hedgehog (Shh), produced by the dopaminergic neurons of the substantia nigra (DA SNpc), are both involved in the nigrostriatal maintenance but the reciprocal neurotrophic relationships among these neurons are only partially understood. To define the postnatal neurotrophic connections among fast‐spiking GABAergic interneurons (FS), cholinergic interneurons (ACh), and DA SNpc, we used a genetically induced mouse model of postnatal DA SNpc neurodegeneration and separately eliminated Smoothened (Smo), the obligatory transducer of Shh signaling, in striatal interneurons. We show that FS postnatal survival relies on DA SNpc and is independent of Shh signaling. On the contrary, Shh signaling but not dopaminergic striatal innervation is required to maintain ACh in the postnatal striatum. ACh are required for DA SNpc survival in a GDNF‐independent manner. These data demonstrate the existence of three parallel but interdependent neurotrophic relationships between SN and striatal interneurons, partially defined by Shh and GDNF. The definition of these new neurotrophic interactions opens the search for new molecules involved in the striatal modulatory circuit maintenance with potential therapeutic value.

Sonic Hedgehog is expressed by hilar mossy cells and regulates cellular survival and neurogenesis in the adult hippocampus

“…A recent study by Ortega et al . 41 confirms the pattern of Shh expression from the wt allele and from the gene expression tracer allele in the nigro-striatal system. Likewise, in the cerebellum, Shh - nlacZ was consistently expressed in large GABAergic neurons known as Purkinje cells (Fig.…”

Parkinson's disease motor symptoms rescue by CRISPRa‐reprogramming astrocytes into GABAergic neurons

“…In addition, most of the basal striatal excitatory drive arising from cholinergic interneurons is balanced by a concomitant GABAergic inhibition; this signaling is impaired by dopamine deprivation (Lozovaya et al , 2018). Furthermore, integrity of the fast spiking striatal GABAergic interneurons has been shown to depend on dopaminergic input from the SN pc (Ortega‐de San Luis et al , 2018). Altogether, these reports as well as our own findings suggest that the imbalance in striatal microcircuitry—including impaired GABAergic signaling—contribute to the altered motor behavior in parkinsonian state.…”

Adult Neurogenesis: A Story Ranging from Controversial New Neurogenic Areas and Human Adult Neurogenesis to Molecular Regulation

“…Table 4 shows a summary of the material presented here. [128,129] In an elegant study, microinfusions of 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), a preferential agonist of the DA D3 receptor, or vehicle (saline) were administered into the ventral third ventricle of female Sprague-Dawley rats. In addition to this treatment, rats received a daily i.p.…”

“…Ortega-de San Luis et al performed a series of experiments to suggest that NTFs are present in the SN. The number of dopaminergic neurons in the SN (diminishing the expression of Shh and other NTFs) was depleted through the deactivation of the mitochondrial Sdhd gene in mice [129]. Animals showed a regular number of DA neurons at birth but suffered DA neurodegeneration postnatally.…”