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.(17 ) The discharge activity of these striatal cells is normally regulated by a balance between an inhibitory nigral dopamine input and an excit atory cortical glutamate input.(24) The loss of nigrostriatal dopamine in Parkinson's disease allows the cortical glutamatergic input to dom inate (see Fig. 1). Pharmacological or surgical manipulations which re dress this imbalance in activity in the striatum, or prevent its propa gation throughout the basal ganglia, alleviate the motor symptoms of P arkinsonism.(2,4,14) We present evidence to suggest the existence of a n endogenous mechanism which compensates for the striatal imbalance du ring the early stages of Parkinsonism. In the rat rendered parkinsonia n by systemic administration of reserpine, selective deletion of stria tal neurons was observed. The dying striatal neurons exhibited all of the morphological and biochemical hallmarks of apoptosis. This apoptot ic cell death was blocked by either administration of glutamate antago nists 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 mechan isms which maintain the balance of neural activity within the CNS and to the pathology of neurological diseases.