Consequences of nigrostriatal denervation on the gamma-aminobutyric acidic neurons of substantia nigra pars reticulata and superior colliculus in parkinsonian syndromes

Abstract

To examine the effects of nigrostriatal denervation on the substantia nigra pars reticulata (SNpr), one of the main outputs of the basal ganglia, we used quantitative in situ hybridization to analyze the messenger RNA coding for Mr 67,000 glutamic acid decarboxylase (GAD67 mRNA) in the SNpr neurons from patients with Parkinson's disease (PD), monkeys rendered parkinsonian by 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), and their respective controls. In MPTP-intoxicated monkeys, the expression of GAD67 mRNA was increased in the SNpr neurons, and the increase was reversed by L-dopa treatment. There were no differences in the level of GAD67 mRNA between PD patients who had been treated with L-dopa and control subjects. Combined with the previously reported increased expression of GAD67 mRNA in the internal segment of the pallidum of MPTP-intoxicated monkeys, these data suggest that the gamma-aminobutyric acid (GABAergic) activity of the output system of the basal ganglia is globally increased by nigrostriatal denervation. We also analyzed the level of GAD67 mRNA expression in the superior colliculus, a structure that receives the inhibitory influence of the GABAergic neurons of the SNpr and that is involved in eye movement control. GAD67 mRNA expression was reduced in both MPTP-intoxicated monkeys, whether or not they received L-dopa therapy, and PD patients, compared to their respective controls. This decrease may result from the hyperactivity of the inhibitory nigrotectal pathway, but also from other influences since it was not corrected by L-dopa therapy. These changes may account for the slight ocular motor and visuospatial cognitive impairment occurring in PD, even after L-dopa therapy.

Glial cell line-derived neurotrophic factor (GDNF) gene expression in the human brain: A post mortem in situ hybridization study with special reference to Parkinson's disease

“…The time interval between the death of the patients and conservation of the brain tissues did not affect G D N F mRNA, since, under similar conditions, the probe allowed detection of G D N F m R N A in a newborn infant striatum also obtained post mortem. In addition, the absence of staining observed in the control and parkinsonian brains used in this study cannot be attributed to a global mRNA degradation since glutamic acid decarboxylase (isoform 67 KD) mRNAs (Levy et al, 1995a;Vila et al, 1996), several glutamate receptors mRNAs (Bernard et al, 1996), substance P and methionin-enkephalin mRNAs (Levy et al, 1995b) have been successfully detected by in situ hybridization in the studied brains. It cannot be excluded however that GDNF mRNA is particularly instable post mortem.…”

Striatal and nigral D 1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats

“…Possibly, the antiparkinsonian effects of D 1 agonists are dependent upon neuronal excitation produced in the cell body (Gonon 1997), as well as modulation of neurotransmitter release at the terminal, the combination of which results in an increase in GABA release in SNr. It has been suggested that the hyperactivity of SNr cells is involved in the production of parkinsonian symptoms (Vila et al 1996), and that the SNr is a critical region for the generation of tremulous movements (Buzsaki et al 1990;Finn et al 1997b;Salamone et al 1998). SNr neuronal activity can be reduced by systemic (Weick et al 1990) or nigral (Timmerman and Abercrombie 1996) administration of a D 1 agonist.…”

Functional anatomy of thalamus and basal ganglia

“…The basal ganglia are organised in such a fashion that nigrostriatal denervation (the hallmark of Parkinson's disease) leads to overactivity of the internal globus pallidus and the substantia nigra pars reticulata (Fig. 4, right) [74,190]. The pathological hyperactivity of both these nuclei and the subthalamic nucleus [191] has been seen as the result of a reduced inhibitory input from the striatum to the direct pathway [109] and increased activity of the indirect pathway [71].…”