Autocrine—paracrine Regulation of Hippocampal Neuron Survival by IGF‐1 and the Neurotrophins BDNF, NT‐3 and NT‐4

Abstract

In contrast to sympathetic and sensory neurons in the peripheral nervous system, the neurotrophic requirements for neurons in the central nervous system (CNS) have not been clearly identified. The inactivation of specific neurotrophic factors and their receptors by gene targeting has shown that there are no major changes in neuron numbers in the CNS. This suggests an overlap between the action of different neurotrophic factors in the brain during development. Here we have studied the survival of hippocampal neurons prepared from embryonic rats using different culture conditions. Whereas the hippocampal neurons survive well in culture when plated at high density, they die at lower cell densities in the absence of appropriate neurotrophic factors. Under the latter conditions, both insulin-like growth factor-1 (IGF-1) and neurotrophins - brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) - rescued a large proportion of cultured neurons. In addition, hippocampal neurons from BDNF knockout mice exhibited enhanced cell death compared with cells from wild-type animals. BDNF and IGF-1 both increased the survival of the hippocampal neurons lacking BDNF, showing complementary action for these factors in supporting survival. Blocking antibodies against NT-3 and IGF-1 decreased hippocampal neuron survival at low cell densities, showing autocrine or paracrine action of the factors. At higher cell densities, however, the antibodies had no effect, demonstrating that there is a sufficient amount of endogenous factors in supporting survival. Blocking antibodies against NT-3 and IGF-1 decreased hippocampal neurons depend for survival on local neurotrophic factors such as IGF-1, BDNF and NT-3, which act in an autocrine/paracrine manner. The multifactorial support of hippocampal neurons ensures a maximal degree of neuron survival even in the absence of an individual factor

NeuroD Regulates Neuronal Migration

“…It has been reported that NeuroD is an upstream regulator of neurotrophin receptors in the differentiating neurons of inner ear (Kim et al, 2001). In the cerebellum, Trk/neurotrophin signaling is essential for the migration, polarization, and survival of the cerebellar granule cells (Borghesani et al, 2002;Lindholm et al, 1996;Minichiello and Klein, 1996). In the hippocampus, TrkB and TrkC signaling cooperate to promote the survival of the DG granular neurons (Minichiello and Klein, 1996).…”

BDNF in schizophrenia, depression and corresponding animal models

“…30 Thus, within the hippocampus, neurons from the BDNF knockout mice exhibited enhanced cell death compared with cells from the wild-type animals. 27 Moreover, exogenous BDNF increased the survival of the hippocampal neurons lacking BDNF. 27 BDNF prevents the spontaneous death of dopaminergic neurons in rat primary mesencephalic cultures 31,32 and protects TH-immunoreactive neurons from the selective toxin MPP þ (1-methyl-4-phenylpyridinium).…”

“…27 Moreover, exogenous BDNF increased the survival of the hippocampal neurons lacking BDNF. 27 BDNF prevents the spontaneous death of dopaminergic neurons in rat primary mesencephalic cultures 31,32 and protects TH-immunoreactive neurons from the selective toxin MPP þ (1-methyl-4-phenylpyridinium). 29 Repeated intrastriatal injections of BDNF protect from damage induced by intrastriatal administration of 6-OHDA, 33 with moderate preserving of striatal dopaminergic nerve endings around the injection site.…”

“…BDNF has survival-promoting actions on a variety of CNS neurons including hippocampal and cortical neurons, 26,27 cholinergic, 28 nigral dopaminergic, 29 and 5-HT neurons. 30 Thus, within the hippocampus, neurons from the BDNF knockout mice exhibited enhanced cell death compared with cells from the wild-type animals.…”

Trophic support promotes survival of bcl-x-deficient telencephalic cells in vitro

“…Although IGF receptor ligands increased survival, apoptosis still occurred in approximately 50% of bcl-x 7/7 cells grown in supplemented media, suggesting that additional factors may promote survival of E12 bcl-x 7/7 telencephalic cells. The effects of a number of neurotrophic factors were tested using concentrations of factors shown previously to have maximal effects on other neuronal cells (Ip et al, 1994;Lin et al, 1993;Lindholm et al, 1996;Knusel et al, 1990;Widmer and Hefti, 1994). Addition of 50 ng ml 71 nerve growth factor (NGF), 25 ng ml 71 brain-derived neurotrophic factor (BDNF), 25 ng ml 71 neurotrophin (NT)-3, 25 ng ml 7 1 NT-4, 25 ng ml 71 ciliary neurotrophic factor (CNTF), 25 ng ml 71 glial-derived neurotrophic factor (GDNF), or 25 ng ml 71 epidermal growth factor (EGF) did not increase bcl-x 7/7 telencephalic cell survival (data not shown).…”