Glutamate-induced apoptosis results in a loss of striatal neurons in the parkinsonian rat.
The motor symptoms of Parkinson's disease are caused by an increase in activity of striatal neurons which project to the globus pallidus. The discharge activity of these striatal cells is normally regulated by a balance between an inhibitory nigral dopamine input and an excitatory cortical glutamate input. The loss of nigrostriatal dopamine in Parkinson's disease allows the cortical glutamatergic input to dominate (see Fig. 1). Pharmacological or surgical manipulations which redress this imbalance in activity in the striatum, or prevent its propagation throughout the basal ganglia, alleviate the motor symptoms of Parkinsonism. We present evidence to suggest the existence of an endogenous mechanism which compensates for the striatal imbalance during the early stages of Parkinsonism. In the rat rendered parkinsonian by systemic administration of reserpine, selective deletion of striatal neurons was observed. The dying striatal neurons exhibited all of the morphological and biochemical hallmarks of apoptosis. This apoptotic cell death was blocked by either administration of glutamate antagonists or decortication. Our data demonstrate that unchecked endogenous glutamate can induce apoptosis of striatal projection neurons in vivo. This observation may have relevance to the neurophysiological mechanisms which maintain the balance of neural activity within the CNS and to the pathology of neurological diseases.
Mitchell
I J
IJ
Lawson
S
S
Moser
B
B
Laidlaw
S M
SM
Cooper
A J
AJ
Walkinshaw
G
G
Waters
C M
CM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology*; D009434:Neural Pathways / Q000473:pathology; D009474:Neurons / Q000187:drug effects*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D012110:Reserpine