Brain-Derived Neurotrophic Factor Is Required for the Establishment of the Proper Number of Dopaminergic Neurons in the Substantia Nigra Pars Compacta

Abstract

Brain-derived neurotrophic factor (BDNF) has been implicated in regulating neuronal survival, differentiation, and synaptic plasticity. Reduced expression of BDNF within the substantia nigra accompanies the deterioration of dopaminergic neurons in Parkinson's disease (PD) patients. Analysis of the effects of long-term BDNF absence from the CNS has been difficult because of the early postnatal lethality of BDNF Ϫ/Ϫ mice. Mice with a floxed BDNF allele were bred with Wnt1-Cre mice to generate Wnt-BDNF KO mice that lack BDNF from the midbrain-hindbrain (MHB). These mice are viable but exhibit hindlimb clutching and poor rotarod performance. Tyrosine hydroxylase (TH)-positive neuron numbers in the substantia nigra pars compacta (SNC) were estimated using stereological methods, revealing a persistent ϳ23% reduction of these cells at postnatal day 21 (P21) in Wnt-BDNF KO mice compared with controls. The diminishment of TH-expressing neurons was present at birth and continued through P120. This deficit appears selective for the dopaminergic population, because at P21, total neuron number within the SNC, defined as neuronal nuclei protein-positive cells, was not significantly reduced. Interestingly, and similar to observations in PD patients, SNC neuron subpopulations are not equally affected. Calbindin-and calretininexpressing SNC populations show no significant difference between Wnt-BDNF KO mice and controls. Thus, BDNF depletion from the MHB selectively leads to reduced TH expression in a subpopulation of neurons, but it remains unclear whether these cells are lost.

RET Is Dispensable for Maintenance of Midbrain Dopaminergic Neurons in Adult Mice

“…Although it is possible that test sensitivity could be an issue concerning the lack of differences between groups, we do not think that is likely. Although it is true that certain rotarod protocols have been found to be useful for demonstrating dopaminerelated sensorimotor deficits in some (Petroske et al, 2001;Baquet et al, 2005;Iancu et al, 2005) but not all (Tillerson et al, 2002;Fleming et al, 2004) mouse models of PD, the pole test has been recently touted as being a highly sensitive test for detecting subtle sensorimotor deficits in mice overexpressing wild-type human ␣-synuclein (Fleming et al, 2004). The results of the pole test did not reveal any differences between Ret RETfloxEGFP/Ϫ : Dat Cre /ϩ and control mice.…”

Global Deprivation of Brain-Derived Neurotrophic Factor in the CNS Reveals an Area-Specific Requirement for Dendritic Growth

“…We explain this discrepancy as secondary to reduced postnatal growth and poor health of bdnf Ϫ/Ϫ analyzed shortly before their death (Cellerino et al, 1997), such as an abnormal development of electrical properties of retinal ganglion cells. The lack of widespread neuronal death should not be taken to imply that BDNF is not necessary for the survival of small neuronal populations in discrete brain nuclei such as subdivisions of the substantia nigra (Baquet et al, 2005) or noradrenergic neurons in a pontine nucleus (Guo et al, 2005).…”

Ethanol–BDNF interactions: Still more questions than answers

“…The highest levels of TrkB are in hippocampus, cerebellum and cortex but target areas for dopamine (DA) neurons also show diffuse TrkB expression. Diencephalic neurons, hypothalamic and midbrain monoaminergic neurons (raphe, locus coeruleus, Substantia Nigra (SN), Ventral Tegmental area (VTA)) express TrkB and respond to BDNF with increased neurotransmitter synthesis and increased survival (Akbarian et al, 2002;Altar et al, 1992;Altar et al, 1994;Altar et al, 1999;Baquet et al, 2005;Madhav et al, 2001). TrkB is expressed on the majority of mesencephalic DA neurons while a subpopulation also produce BDNF (Numan and Seroogy, 1999).…”