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

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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 ofBDNF-/-mice. Mice with a floxed BDNF allele were bred withWnt1-Cremice to generateWnt-BDNFKOmice 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 ∼23% reduction of these cells at postnatal day 21 (P21) inWnt-BDNFKOmice 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 calretinin-expressing SNC populations show no significant difference betweenWnt-BDNFKOmice 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.