Abstract
Abnormalities of striatal glutamate neurotransmission may play a role in the pathophysiology of Parkinson's disease and may respond to neurosurgical interventions, specifically stimulation or lesioning of the subthalamic nucleus (STN). The major glutamatergic afferent pathways to the striatum are from the cortex and thalamus, and are thus likely to be sources of striatal neuronally-released glutamate. Corticostriatal terminals can be distinguished within the striatum at the electron microscopic level as their synaptic vesicles contain the vesicular glutamate transporter, VGLUT1. The majority of terminals which are immunolabeled for glutamate but are not VGLUT1 positive are likely to be thalamostriatal afferents. We compared the effects of short term, high frequency, STN stimulation and lesioning in 6-hydroxydopamine (6OHDA)-lesioned rats upon striatal terminals immunolabeled for both presynaptic glutamate and VGLUT1. 6OHDA lesions resulted in a small but significant increase in the proportions of VGLUT1-labeled terminals making synapses on dendritic shafts rather than spines. STN stimulation for one hour, but not STN lesions, increased the proportion of synapses upon spines. The density of presynaptic glutamate immuno-gold labeling was unchanged in both VGLUT1-labeled and -unlabeled terminals in 6OHDA-lesioned rats compared to controls. Rats with 6OHDA lesions+STN stimulation showed a decrease in nerve terminal glutamate immuno-gold labeling in both VGLUT1-labeled and -unlabeled terminals. STN lesions resulted in a significant decrease in the density of presynaptic immuno-gold-labeled glutamate only in VGLUT1-labeled terminals. STN interventions may achieve at least part of their therapeutic effect in PD by normalizing the location of corticostriatal glutamatergic terminals and by altering striatal glutamatergic neurotransmission.
Highlights
Deep brain stimulation (DBS) and lesioning of basal ganglia targets have become state-of-the-art therapies for selected patients with moderately advanced Parkinson’s disease (PD)
In order to determine the neuronal source of these changes in glutamate, and to provide insights into alterations in basal ganglia functioning in this situation we performed electron microscopic (EM) studies using immuno-gold to label glutamate [4] and antibodies against the glutamate transporter VGLUT1 to identify corticostriatal afferents [5,6,7,8]
We studied the localization of VGLUT1-labeled synaptic terminals in 6OHDAlesioned rats, and following short term, high frequency subthalamic nucleus (STN) stimulation and STN lesions
Summary
Deep brain stimulation (DBS) and lesioning of basal ganglia targets have become state-of-the-art therapies for selected patients with moderately advanced Parkinson’s disease (PD). The mechanisms by which neurosurgical interventions improve the symptoms of PD are not well understood - whether clinical benefit is achieved by neuronal excitation, inhibition, modulation, or some combination of these. Stimulation and lesioning have similar, but not identical, clinical effects. The effects of lesioning are by definition inhibitory, as neuronal structures are destroyed, but there is evidence to support both inhibitory and excitatory mechanisms of stimulation at the neuronal level [1,2]. In order to determine the neuronal source of these changes in glutamate, and to provide insights into alterations in basal ganglia functioning in this situation we performed electron microscopic (EM) studies using immuno-gold to label glutamate [4] and antibodies against the glutamate transporter VGLUT1 to identify corticostriatal afferents [5,6,7,8]
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