BDNF and NT-4/5 exert neurotrophic influences on injured adult spinal motor neurons

Abstract

Adult motor neurons, like their immature antecedents, express the mRNA for the signaling receptor for brain-derived neurotrophic factor (BDNF) and for neurotrophin-4/5 (NT-4/5). However, while both BDNF and NT-4/5 support the survival of axotomized developing spinal motor neurons in vitro or in vivo, it is not known whether these factors continue to influence spinal motor neurons in adulthood. The present study tests if BDNF or NT-4/5 modulate the reactive responses of adult spinal motor neurons to nerve injury. We utilize sciatic nerve transection to axotomize the spinal motor neurons that form the retrodorsal lateral nucleus (RDLN) and show that, after axotomy, RDLN motor neurons lose ChAT immunoreactivity and also reexpress p75Ingfr, the low affinity receptor for all neurotrophin family members. Treatment with BDNF or NT- 4/5 alters these effects of sciatic nerve transection. Both BDNF and NT- 4/5 attenuate the loss of ChAT expression in axotomized RDLN motor neurons; thus, as compared to vehicle treatments, BDNF and NT-4/5 produce statistically significant increases in the optical density of ChAT immunostaining. Furthermore, BDNF and NT-4/5 also significantly increase the RDLN reexpression of p75Ingfr after sciatic nerve transection. Interestingly, essentially identical increases in RDLN ChAT and p75Ingfr immunostaining are produced by sciatic nerve crush injuries in the absence of exogenous neurotrophin treatment. These data show that treatment with exogenous BDNF and NT-4/5 changes the response of adult spinal motor neurons to sciatic nerve transection. Furthermore, these neurotrophins elicit reactive responses in axotomized motor neurons that mimic those produced by endogenous agents in regenerating crushed peripheral nerve.

Long-Term Adeno-Associated Viral Vector-Mediated Expression of Truncated TrkB in the Adult Rat Facial Nucleus Results in Motor Neuron Degeneration

“…Loss of cholinergic phenotype of axotomized mature motor neurons and rescue thereof by exogenous TrkB ligands is well documented (Yan et al, 1994;Friedman et al, 1995;Wang et al, 1997;Fernandes et al, 1998). Loss of NeuN expression occurs in axotomized facial motor neurons but not in axotomized rubrospinal neurons (McPhail et al, 2004a).…”

“…Cholinergic marker expression in injured adult motor neurons is regulated by exogenously applied TrkB ligands (Yan et al, 1994;Friedman et al, 1995;Tuszynski et al, 1996;Wang et al, 1997;Fernandes et al, 1998). To determine whether overexpression of TrkB isoforms affected the expression of neuronal markers in mature facial motor neurons, we stained sections of AAVinjected animals with an antibody for NeuN, a nuclear protein with DNA binding properties (Mullen et al, 1992), and an antibody for the neurotransmitter synthesizing enzyme ChAT.…”

“…NT-4/5 is the predominant neurotrophin expressed in the targets of mature facial and spinal motor neurons Funakoshi et al, 1995;Griesbeck et al, 1995). Adult motor neurons remain responsive to BDNF, because exogenously applied TrkB ligands maintain the cholinergic phenotype of axotomized adult facial, spinal, and hypoglossal motor neurons (Yan et al, 1994;Friedman et al, 1995;Tuszynski et al, 1996;Wang et al, 1997;Fernandes et al, 1998) and rescue avulsed motor neurons from injury-induced cell death Kishino et al, 1997;Novikov et al, 1997).…”

Cellular and Molecular Pathways of Ischemic Neuronal Death

“…The neuroprotective effects of neurotrophins have been demonstrated under various pathological conditions. For example, neurotrophins protect various populations of neurons from axotomy (Hefti, 1986;Yan et al, 1992;Mey and Thanos, 1993;Chiu et al, 1994;Cohen et al, 1994;Mansour-Robaey et al, 1994;Friedman et al, 1995). Neurotrophins can attenuate neuronal death following global or focal cerebral ischemia (Shigeno et al, 1991;Beck et al, 1994;Chan, 1996).…”

Targeted Transduction of CNS Neurons with Adenoviral Vectors Carrying Neurotrophic Factor Genes Confers Neuroprotection That Exceeds the Transduced Population

“…C iliary neurotrophic factor (C N TF), a member of the neuropoietin family, brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, and glial cell line-derived neurotrophic factor (GDN F), a member of the Transforming Growth Factor ␤ (TGF-␤) family, all have demonstrable neuronal survival activity in vivo. Application of any one of these NFs to the proximal stump of a cut facial nerve or sciatic nerve of a neonatal rat protects the facial nucleus and spinal cord motoneurons, respectively, from axotomy-induced death (Sendtner et al, 1990(Sendtner et al, , 1992Yan et al, 1992;Koliatsos et al, 1993;Henderson et al, 1994;Friedman et al, 1995;Li et al, 1995). Under other conditions neurons may be stimulated by target-derived NFs to themselves express N Fs that may, in turn, act both in an autocrine/paracrine manner (Schecterson and Bothwell, 1992).…”