Monoaminergic regulation of Sonic hedgehog signaling cascade expression in the adult rat hippocampus

Abstract

Monoamines are implicated in the modulation of adult hippocampal neurogenesis in depression models and following chronic antidepressant treatment. Given the key role of Sonic hedgehog (Shh) in adult neurogenesis, we examined whether monoaminergic perturbations regulate the expression of Shh or its co-receptors Smoothened (Smo) and Patched (Ptc). Combined depletion of both serotonin and norepinephrine with para-chlorophenylalanine (PCPA) resulted in a significant decrease in Smo and Ptc mRNA within the dentate gyrus subfield of the hippocampus. However, selective depletion of serotonin, using the serotonergic neurotoxin 5,7-dihyrdroxytryptamine (5,7-DHT), or norepinephrine, using the noradrenergic neurotoxin DSP-4, did not alter expression of Shh and its co-receptors, Smo and Ptc. Acute treatment with the monoamine releasing agent, para-chloroamphetamine (PCA) significantly upregulated Smo mRNA within the dentate gyrus. However, acute or chronic treatment with pharmacological antidepressants that modulate monoaminergic neurotransmission did not regulate Shh cascade expression. These results indicate that robust changes in monoamine levels can regulate the expression of the Shh signaling cascade in the adult rodent brain.

Fig. 1

Influence of PCPA & PCA treatment on the expression of the Shh cascade in the adult rat brain. Rats were administered either PCPA, PCA or vehicle (VEH) treatment in separate experiments, and levels of Shh, Smo and Ptc mRNA were determined by in situ hybridization and quantitative densitometry. PCPA treatment decreased the expression of Smo and Ptc mRNA in the dentate gyrus (DG), but did not influence Shh mRNA expression in the Horizontal limb/Vertical limb of the Diagonal Band (VDB)—Upper Panel. PCA treatment significantly increased the levels of Smo mRNA in the DG, but did not alter the levels of Ptc mRNA in the DG or Shh in the VDB/HDB region—Lower Panel. Representative autoradiographs of Shh, Smo and Ptc mRNA from vehicle and PCPA treated animals (Upper Panel) and vehicle and PCA treated animals (Lower Panel) are shown. Results are expressed as percent of vehicle and are the mean ±S.E.M. (n = 5 /group); ^*p < 0.05 as compared with vehicle (Student's t-test).

Fig. 2

Influence of DSP-4 and 5,7-DHT treatment on the expression of the Shh cascade in the rat brain. Rats received treatment with vehicle (VEH), DSP-4 or 5,7-DHT in separate experiments, and levels of Shh, Smo and Ptc mRNA were determined with in situ hybridization and quantitative densitometry. DSP-4 or 5,7-DHT treatment did not influence Shh mRNA expression in the Horizontal limb/Vertical limb of the Diagonal Band (VDB) or the expression of the Shh receptors, Smo and Ptc in the hippocampal dentate gyrus (DG) subfield. Representative autoradiographs of Shh, Smo and Ptc mRNA from vehicle and DSP-4 (Upper Panel), and vehicle and 5,7-DHT (Lower Panel) treated animals are shown. Results are expressed as percent of vehicle and are the mean ±S.E.M. (n = 5/group).