Dopamine receptor supersensitivity in rat subthalamus after 6‐hydroxydopamine lesions

Abstract

The subthalamic nucleus (STN) receives direct dopaminergic innervation from the substantia nigra pars compacta, but the importance of this input in the pathophysiology of parkinsonism remains to be determined. We used whole-cell patch-clamp recordings in brain slices to study presynaptic dopaminergic modulation of synaptic inputs to the STN in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. Here, we report that dopamine was more potent for inhibiting GABA IPSCs and glutamate EPSCs in the STN ipsilateral to the lesion, and was less potent for suppressing IPSCs and EPSCs in the STN contralateral to the lesion, compared with the effects of dopamine in control STN. Dopamine reduced IPSCs with an IC50 value of 20.9 +/- 3.6 microM in control STN, whereas IC50 values were 0.83 +/- 0.15 and 55.1 +/- 11.1 microM in STN ipsilateral and contralateral to 6-OHDA lesions, respectively. Dopamine also inhibited EPSCs with an IC50 value of 12.8 +/- 2.8 microM in control STN, whereas IC50 values were 4.5 +/- 0.9 and 41.6 +/- 9.8 microM in STN ipsilateral and contralateral to 6-OHDA lesions, respectively. Results with paired stimuli to evoke EPSCs and IPSCs suggest that endogenous dopamine acts presynaptically to inhibit transmitter release in the STN. These results show that chronic dopamine denervation significantly alters the regulation of synaptic input to the STN. Our results also suggest that the STN may be an important target for levodopa therapy in Parkinson's disease.

Pallidal Origin of GABA Release within the Substantia Nigra Pars Reticulata during High-Frequency Stimulation of the Subthalamic Nucleus

“…The change in SNr Glu levels after dopaminergic denervation may be attributable to an effect restricted to the STN or related structures. Many studies have reported direct dopaminergic innervation of the STN (Brown et al, 1979;Meibach and Katzman, 1979;Campbell et al, 1985;Hassani et al, 1997;Smith et al, 1998), which may control STN neuron activity directly or via presynaptic modulation of neurotransmitter release (Kreiss et al, 1997;Ni et al, 2001;Shen et al, 2003;Cragg et al, 2004). The level of GABA in the SNr also increased in hemiparkinsonian rats.…”

A population level computational model of the basal ganglia that generates parkinsonian local field potential activity

“…The cortical projection to the striatum is thought to be modified in PD, toward weakened and enhanced influences to the D1 and the D2 segments, respectively (West and Grace 2002). In the STN, both inhibitory and excitatory projections seem to be enhanced under dopamine-depleted states (Shen and Johnson 2000;Shen et al 2003;Floran et al 2004). Finally, in the GPe, it has been found that the inhibitory connection from the striatum is enhanced in such states (Cooper and Stanford 2001), and the input from the STN is hyperactive (Johnson and Napier 1997).…”

NG2 Glia: Novel Roles beyond Re-/Myelination

“…The release of the NG2 ectodomain from NG2 glia was augmented by treatments with depolarizing agents or glutamate in vitro [98]. Along this line, the expression of the neuromodulatory/neuroprotective peptide galanin significantly increased in NG2 glia upon experimental cortical spreading depression [169]. These observations suggest that activity dependent/synapse-mediated signals converging on NG2 glia may dynamically regulate their secretory activity and homeostatic functions.…”

“…study and CM of cultured rat NG glia [165] Synaptogenesis and synaptic plasticity [166], oligodendroglial and neuronal survival [167,168] Galanin mRNA and protein expr. in adult mouse NG2 glia [169] Modulation of neuronal activity [170] Chromogranin B, Chgb Gene expr. study of freshly sorted adult human NG2 glia [125] Neurotransmission [171,172] Chromogranin C, Chgc Gene expr.…”