, 2005; Tsuboi and Shults, 2002). In these paradigms, the neuroprotective effect of Shh on mesencephalic DA neurons is comparable to that observed with striatal delivery of GDNF (Dass et al., 2002). In vitro, Shh synergizes with neural growth factor (NGF) in providing trophic support to basal forebrain-derived, postnatal ACh neurons (Reilly et al., 2002). Despite these observations, it

is not clear whether there is a functionally relevant source of Shh that could act in the mature mesostriatal system and if so, which cell types would communicate by Shh signaling. Here, we present evidence for reciprocal, trophic factor signaling between mesencephalic DA, striatal ACh, and FS neurons. We show that DA neurons

utilize Shh to signal to ACh and FS interneurons INCB024360 datasheet in the striatum where it regulates extracellular ACh tone, expression of GDNF, and maintenance of these neurons. Conversely, Shh expression by DA neurons is repressed by signals that originate from ACh neurons and engage the canonical selleck kinase inhibitor GDNF receptor Ret on DA neurons. The conditional ablation of Shh from DA neurons results in a progressive model of PD with face, construct and predictive validity. Thus, our results shed light onto aspects of the chemical neuroanatomy of the basal ganglia and may have far-reaching implications for the understanding of the physiopathology and the treatment of movement disorders such as PD. To examine whether Shh-mediated signaling occurs among neurons of the mesostriatal circuit, we first visualized expression of Shh in the adult brain using mice heterozygous for a conditional, gene expression tracer allele of Shh (Shh-nLZC/+) ( Figure S1A available online). We observed Shh expression by all tyrosine hydroxylase-positive (Th+) neurons in the substantia nigra pars compacta (SNpc) (

Figures 2A and 2B), the ventral tegmental area (VTA) ( Figure 2A), and the retrorubral field (RRF, data not shown) along the entire rostro-caudal axis of these nuclei at 3 months of age Org 27569 (100 ± 0%, 683 cells, n = 2). We did not observe Shh expression by Th+ neurons of the diencephalon or olfactory bulb or by cells in the striatum (data not shown). To determine whether Shh signaling within the mesostriatal circuit is of physiological relevance, we selectively ablated Shh expression from DA neurons mediated by Cre activity expressed from the DA transporter locus (Dat-Cre; all mouse strains used in this study are referenced in Supplemental Experimental Procedures). Shh-nLZC/C/Dat-Cre mutant animals were born alive and mobile with expected Mendelian frequency and no overt structural or motor signs at the end of postnatal development compared to Shh-nLZC/+/Dat-Cre control littermates ( Figures S1 and S2; Table S1; Supplemental Results A and B; for all comparative analyses herein littermates double heterozygous for Shh-nLZC/+and Dat-Cre served as controls).