Molecular Neurobiology

, Volume 12, Issue 1, pp 73-94

First online:

Glutamate and Parkinson’s disease

  • Fabio BlandiniAffiliated withNeurological Institute “C. Mondino,”, University of Pavia
  • , Richard H. P. PorterAffiliated withUniversity Department of Clinical Neuropathology
  • , J. Timothy GreenamyreAffiliated withDepartments of Neurology and PharmacologyYerkes Regional Primate Research Center, Emory University School of Medicine

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Altered glutamatergic neurotransmission and neuronal metabolic dysfunction appear to be central to the pathophysiology of Parkinson’s disease (PD). The substantia nigra pars compacta—the area where the primary pathological lesion is located—is particularly exposed to oxidative stress and toxic and metabolic insults. A reduced capacity to cope with metabolic demands, possibly related to impaired mitochondrial function, may render nigral neurons highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. In this way, glutamate may participate in the pathogenesis of PD. Degeneration of dopamine nigral neurons is followed by striatal dopaminergic denervation, which causes a cascade of functional modifications in the activity of basal ganglia nuclei. As an excitatory neurotransmitter, glutamate plays a pivotal role in normal basal ganglia circuitry. With nigrostriatal dopaminergic depletion, the glutamatergic projections from subthalamic nucleus to the basal ganglia output nuclei become overactive and there are regulatory changes in glutamate receptors in these regions. There is also evidence of increased glutamatergic activity in the striatum. In animal models, blockade of glutamate receptors ameliorates the motor manifestations of PD. Therefore, it appears that abnormal patterns of glutamatergic neurotransmission are important in the symptoms of PD. The involvement of the glutamatergic system in the pathogenesis and symptomatology of PD provides potential new targets for therapeutic intervention in this neuro-degenerative disorder.

Index Entries

Basal ganglia excitotoxicity excitatory amino acids bioenergetics N-methyl-D-aspartate