The TrkB-Positive Dopaminergic Neurons are Less Sensitive to MPTP Insult in the Substantia Nigra of Adult C57/BL Mice

Abstract

Tyrosine kinase receptors TrkB and TrkC mediate neuroprotective effects of the brain-derived neurotrophic factor (BDNF) and neurotrophins in the dopaminergic nigro-striatal system, but it is obscure about their responses or expression changes in the injured substantia nigra under Parkinson's disease. In present study, immunofluorescence, Fluoro-Jade staining and laser scanning confocal microscopy were applied to investigate distribution and changes of TrkB and TrkC in the dopamine neurons of the substantia nigra by comparison of control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. It revealed that TrkB and TrkC-immunoreactivities were substantially localized in cytoplasm and cell membrane of the substantia nigra neurons of control adults. While neurons double-labeled with tyrosine hydroxylase (TH)/TrkB, or TH/TrkC were distributed in a large numbers in the substantia nigra of controls, they apparently went down at 36.2-65.7% of normal level, respectively following MPTP insult. In MPTP model, cell apoptosis or degeneration of nigral neurons were confirmed by caspase-3 and Fluoro-Jade staining. More interestingly, TH/TrkB-positive neurons survived more in cell numbers in comparison with that of TH/TrkC-positive ones in the MPTP model. This study has indicated that TrkB-containing dopamine neurons are less sensitive in the substantia nigra of MPTP mouse model, suggesting that specific organization of Trks may be involved in neuronal vulnerability to MPTP insult, and BDNF-TrkB signaling may play more important role in protecting dopamine neurons and exhibit therapeutic potential for Parkinson's disease.

Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies

“…However, there is an important shift in the subcellular distribution of TrkB-FL and TrkB-T1 in PD SNpc and striatum [125], being prominent a decrease of the catalytic receptor isoform in dendrites indicative of impaired synaptic function. Nonetheless, the deficiency in BDNF/TrkB survival signalling increases the susceptibility of SN dopaminergic neurons to cytotoxic injury [126,127] and might contribute to PD development. Actually, inhibition of BDNF expression or TrkB insufficiency cause selective loss of SNpc dopaminergic neurons [128,129,130] and exacerbate motor dysfunction in aged animals [131].…”

Age-related gene expression changes in substantia nigra dopamine neurons of the rat

“…We found that expression of TrkB mRNA (encoded by the Ntrk2 gene), but not Bdnf itself, was significantly reduced in SNpc DA neurons from old animals, although no change in TrkB was observed in the striatum. Previous studies have shown that changes in Bdnf expression or lack of TrkB expression increases the susceptibility of SN DA neurons to cytotoxic injury (Ding et al, 2011;Hung and Lee, 1996;Levivier et al, 1995;Shults et al, 1995;Fletcher-Turner, 2000, 2001). Furthermore, deprivation of Bdnf or TrkB has been shown to exacerbate motor dysfunction and impair DA uptake and neuronal survival in aged animals (Baydyuk et al, 2011;Boger et al, 2011;Porritt et al, 2005;Saylor et al, 2006), suggesting that the combination of ageing and TrkB deprivation are detrimental to SN neuronal survival.…”

Omega‐3 fatty acid eicospentaenoic acid attenuates MPP+‐induced neurodegeneration in fully differentiated human SH‐SY5Y and primary mesencephalic cells

“…; Ding et al . ), and partial deletion of the TrkB receptor leads to a reduced number of dopaminergic cells in the SN and the formation of α‐synuclein aggregates in older mice (Von Bohlen und Halbach et al . ).…”

“…; Ding et al . ). The primary mode of cell death in PD is apoptosis (Dauer and Przedborski ), possibly induced by oxidative stress and inflammation.…”