Early Developmental Destruction of Terminals in the Striatal Target Induces Apoptosis in Dopamine Neurons of the Substantia Nigra

Abstract

Many developing neural systems with peripheral projections depend on their target for trophic support during a critical period of natural cell death. Much less is known about central systems. That dopaminergic neurons of the substantia nigra may depend on their target, the striatum, during development is suggested by the presence of a natural apoptotic cell death event in these neurons that can be augmented by an early developmental axon-sparing striatal injury. To further assess the target dependence of these neurons, we have used the selective neurotoxin 6-hydroxydopamine to lesion their terminals within the striatum during development, while sparing intrinsic striatal target neurons. This lesion results in an induction of apoptotic cell death in phenotypically defined dopaminergic neurons that appears on the third postlesion day and persists until the tenth. This inducibility of cell death is dependent on developmental age: it is most marked before postnatal day (PND) 14. As late as PND42, inducibility is still detectable but much less so. In addition, at day 42 the morphology of cell death changes and becomes nonapoptotic in some cells. We conclude that terminal injury during a critical period of postnatal development, like axon-sparing target injury, induces augmented apoptotic death in mesencephalic dopaminergic neurons. These results suggest that these neurons have a period of target dependence. Regulation of this dependence is likely to influence the mature adult number of dopaminergic neurons.

Glial Cell Line-Derived Neurotrophic Factor Is Essential for Postnatal Survival of Midbrain Dopamine Neurons

“…The extent of apoptosis in many central and peripheral neuronal populations, including midbrain DA neurons, depends on target innervation and/or trophic factor exposure. (Kelly and Burke, 1996;Haviv et al, 1997;Marti et al, 1997). Because GDNF has been demonstrated to be a target-derived trophic factor (Ström-berg et al, 1993;Tomac et al, 1995), it is more likely to exert survival-promoting activity on DA neurons during the time of target innervation rather than during earlier fetal development, when phenotypic differentiation occurs (Marti et al, 1997).…”

“…(Kelly and Burke, 1996;Haviv et al, 1997;Marti et al, 1997). Because GDNF has been demonstrated to be a target-derived trophic factor (Ström-berg et al, 1993;Tomac et al, 1995), it is more likely to exert survival-promoting activity on DA neurons during the time of target innervation rather than during earlier fetal development, when phenotypic differentiation occurs (Marti et al, 1997). Indeed, in situ hybridization studies have shown prominent GDNF mRNA expression in striatum during the first 2 postnatal weeks in the rat, the time during which connectivity between dopamine afferent fibers and striatal neurons develops in this species, and also the time period when the major apoptotic events occur in these neurons (Strömberg et al, 1993;Marti et al, 1997;Oo and Burke, 1997).…”

“…Because GDNF has been demonstrated to be a target-derived trophic factor (Ström-berg et al, 1993;Tomac et al, 1995), it is more likely to exert survival-promoting activity on DA neurons during the time of target innervation rather than during earlier fetal development, when phenotypic differentiation occurs (Marti et al, 1997). Indeed, in situ hybridization studies have shown prominent GDNF mRNA expression in striatum during the first 2 postnatal weeks in the rat, the time during which connectivity between dopamine afferent fibers and striatal neurons develops in this species, and also the time period when the major apoptotic events occur in these neurons (Strömberg et al, 1993;Marti et al, 1997;Oo and Burke, 1997). Supporting the hypothesis of GDNF as a survival factor for dopamine neurons, we have recently shown that combined treatment with GDNF and caspase inhibitors enhances DA cell survival and fiber outgrowth in fetal VM grafts from normal fetal rat donors into the anterior eye chamber of adult rats .…”

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

“…As envisioned by classic neurotrophic theory (Clarke, 1985;Barde, 1989), this death event appears to be regulated by target interactions; it is augmented by disruption of such interactions by a target lesion (Macaya et al, 1994), DA terminal destruction (Marti et al, 1997), or axotomy (El-Khodor and Burke, 2002) during the first 2 weeks of life. We have evaluated the possibility that GDNF may serve as a physiological, limiting, target-derived factor for SN DA neurons.…”

Apoptotic natural cell death in developing primate dopamine midbrain neurons occurs during a restricted period in the second trimester of gestation

“…Sections were mounted onto glass slides and lightly counterstained for Nissl substance using thionin to visualize nuclei and nucleoli. Apoptotic profiles were counted only if they fulfilled the criteria of having, in the same focal plane, both chromatin clumps within the nucleus together with TH-ir in the cytoplasm (Marti et al, 1997).…”