Protection against dopaminergic nigrostriatal cell death by excitatory input ablation.
The importance of enhanced glutamatergic neurotransmission in the basal ganglia and related structures has recently been highlighted in the development of Parkinson's disease. The pedunculopontine tegmental nucleus (PPN) is the major origin of excitatory, glutamatergic input to dopaminergic nigrostriatal neurons of which degeneration is well known to cause Parkinson's disease. Based on the concept that an excitatory mechanism mediated by glutamatergic neurotransmission underlies the pathogenesis of neurodegenerative disorders, we made an attempt to test the hypothesis that removal of the glutamatergic input to the nigrostriatal neurons by PPN lesions might prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the macaque monkey. The PPN was lesioned unilaterally with microinjection of kainic acid, and, then, MPTP was administered systemically. In these monkeys, the degree of parkinsonian motor signs was behaviourally evaluated, and the histological changes in the dopaminergic nigrostriatal system were analysed by means of tyrosine hydroxylase immunohistochemistry. The present results revealed that nigrostriatal cell loss and parkinsonian motor deficits were largely attenuated in the MPTP-treated monkey group whose PPN had been lesioned, compared with the control, MPTP-treated monkey group with the PPN intact. This clearly indicates that the onset of MPTP neurotoxicity is suppressed or delayed by experimental ablation of the glutamatergic input to the nigrostriatal neurons. Such a protective action of excitatory input ablation against nigrostriatal cell death defines evidence that nigral excitation driven by the PPN may be implicated in the pathophysiology of Parkinson's disease.
Takada
M
M
Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan. takada@tmin.ac.jp
Matsumura
M
M
Kojima
J
J
Yamaji
Y
Y
Inase
M
M
Tokuno
H
H
Nambu
A
A
Imai
H
H
D000818:Animals; D016923:Cell Death; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D005260:Female; D007839:Functional Laterality; D007608:Kainic Acid / Q000633:toxicity; D020267:MPTP Poisoning / Q000503:physiopathology*; D008251:Macaca; D008297:Male; D008845:Microinjections; D009043:Motor Activity; D011149:Pons / Q000502:physiology; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D013477:Superior Colliculi / Q000502:physiology; D013681:Tegmentum Mesencephali / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
D007608:Kainic Acid; D004298:Dopamine