A Role for TrkA during Maturation of Striatal and Basal Forebrain Cholinergic NeuronsIn Vivo

Abstract

Nerve growth factor (NGF), acting via the TrkA receptor, has been shown to regulate the survival and maturation of specific neurons of the peripheral nervous system. Furthermore, exogenous NGF has potent actions on TrkA-expressing cholinergic neurons of the basal forebrain (BFCNs) and striatum. However, initial analysis of mice lacking NGF or TrkA revealed that forebrain cholinergic neurons were present in these animals through the fourth postnatal week. Because of the potential effects of NGF/TrkA interactions on these developing neurons, we have analyzed quantitatively the striatal and basal forebrain cholinergic neurons in trkA knock-out mice. By postnatal day (P) 7/8, forebrain cholinergic neurons are smaller in trkA (Ϫ/Ϫ) mice than those in wild-type littermate controls. However, cholinergic neuron number and fiber density in the hippocampus, a target region of BFCNs, are grossly intact. Interestingly, by P20-P25 trkA knock-outs contain significantly fewer (20-36%) and smaller cholinergic neurons in both the striatum and septal regions, as compared with controls. Cholinergic fiber density within the hippocampus also is depleted in knock-outs by the end of the second postnatal week. Contrary to some predictions, despite expression of p75 NTR in the absence of trkA in BFCNs of these knock-out mice, many cells, although smaller, are still alive at P25. Our data suggest that, in the absence of NGF/TrkA signaling, striatal cholinergic neurons and BFCNs do not mature fully and that BFCNs begin to atrophy and/or die surrounding the time of target innervation.

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

“…Of particular relevance to our discussion of cholinergic signaling and schizophrenia are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and cortical steroids. NGF, BDNF, and glucocorticoids regulate the expression of ChAT, enhance the connectivity of, and promote the survival of cholinergic neurons (Fagan et al, 1997;Grosse et al, 2005;Guijarro et al, 2006;Johnston et al, 1987;Mobley et al, 1986;Phillips et al, 2004;Sofroniew et al, 2001;Takahashi, 1998;Takahashi and Goh, 1998;Ward and Hagg, 2000). Reports have demonstrated altered regulation of NGF (Parikh et al, 2003), BDNF (Weickert et al, 2003(Weickert et al, , 2005, and the HPA axis (Corcoran et al, 2001(Corcoran et al, , 2003 in schizophrenics.…”

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

“…Understanding the mechanisms underlying neuronal cell death and the means by which it can be prevented may lead to better treatments. The neurotrophins (NTs), including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, and NT-4/5, make up a family of neurotrophic factors that are important regulators of naturally occurring cell death in the peripheral nervous system (PNS) (Chao, 1992;Snider, 1994) and also regulate neuronal development and maturation in the CNS (Chen et al, 1997;Fagan et al, 1997;Martinez et al, 1998). Survival-promoting effects of neurotrophins are elicited by activation of different intracellular signaling cascades including the phosphatidylinositol 3-kinase (PI3-kinase) and the extracellular signal-related kinase (ERK) pathways.…”

Tumor Necrosis Factor α Regulates Responses to Nerve Growth Factor, Promoting Neural Cell Survival but Suppressing Differentiation of Neuroblastoma Cells

“…However, it is uncertain whether NGF can contribute to neural cell differentiation under normal conditions of development. First, mice lacking the NGF receptor gene, TrkA, still show normal differentiation of neurons, although the differentiated neurons in these mice contain lower amounts of acetylcholine and gradually disappeared (Fagan et al, 1997;Schober et al, 1997). Second, expression of NGF receptors starts at the late phase of neural differentiation Davies, 1993, 1995;v Holst et al, 1997).…”

“…NGF is secreted from target tissues during development, and neurons extend neurites in the direction of the secreted NGF. Although excessive numbers of neurons are produced during development, only neurons that obtain a sufficient level of NGF can survive and interact with the target tissues (Fagan et al, 1997;Reichardt, 2001, 2003;Sofroniew et al, 2001). Activation of the phosphatidylinositol 3-kinase-Akt signaling pathway by NGF contributes to this NGF-dependent survival (Datta et al, 1999).…”

“…However, neurons that fail to obtain a sufficient level of NGF during development die through an apoptotic pathway (Fagan et al, 1997;Reichardt, 2001, 2003;Sofroniew et al, 2001). Tumor necrosis factor ␣ (TNF-␣) is a cytokine that contributes to this neural cell death (Barker et al, 2001).…”