Elsevier

Neuroscience

Volume 120, Issue 4, 15 September 2003, Pages 1027-1035
Neuroscience

Changes in GABAB RECEPTOR mRNA expression in the rodent basal ganglia and thalamus following lesion of the nigrostriatal pathway

https://doi.org/10.1016/S0306-4522(03)00418-4Get rights and content

Abstract

Loss of striatal dopaminergic innervation in Parkinson's disease (PD) is accompanied by widespread alterations in GABAergic activity within the basal ganglia and thalamus. Accompanying changes in GABAB receptor binding have been noted in some basal ganglia regions in parkinsonian primates, suggesting that plasticity of this receptor may also occur in PD. However, the molecular mechanisms underlying the changes in receptor binding and the manner and extent to which different GABAB receptor mRNA subunits and splice-variants are affected remain unknown. This study used in situ hybridisation to examine the full profile of changes in expression of the known rat GABAB receptor genes and gene variants in the basal ganglia and thalamus of rats, brought about by degeneration of the nigrostriatal tract. All of the GABAB mRNA species examined showed unique expression patterns throughout the basal ganglia and thalamus. In addition, all exhibited a marked loss of expression (between 46 and 80%) in the substantia nigra pars compacta of animals bearing a complete 6-hydroxydopamine-induced lesion of the nigrostriatal tract, confirming the presence of these variants in dopaminergic neurones in this region. Further analysis of autoradioagrams revealed additional changes only in GABAB(1a) mRNA in discrete anatomical regions. Expression of the GABAB(1a) variant was significantly increased in the substantia nigra pars reticulata (33±2%), entopeduncular nucleus (26±1%) and the subthalamic nucleus (16±1%). Since these regions all receive reduced GABAergic innervation following nigrostriatal tract lesioning, it is possible that the increased expression occurs as a compensatory measure. In conclusion, these data demonstrate that GABAB receptor genes exhibit regional- and subunit/variant-specific plasticity at the molecular level under parkinsonian conditions.

Section snippets

Production of 6-OHDA or sham lesions of the nigrostriatal tract

All procedures were carried out in accordance with the U.K. Animals (Scientific Procedures) Act, 1986 and all efforts were made to keep animal suffering and the number of animals used to a minimum. Male, Sprague–Dawley rats (Tucks, Southend-on-Sea, UK) weighing 250–270 g were housed in a light- (12-h light/dark cycle) and humidity-controlled environment with free access to food and water. Thirty minutes prior to surgery animals were dosed with pargyline (5 mg kg−1 i.p.) and desipramine (25 mg kg

Lesion verification

In the 6-OHDA-lesioned group, six of the animals produced at least four rotations/min−1 consistent with a >90% lesion of the nigrostriatal tract (Hefti et al., 1980). In these animals, net contraversive rotations were significantly greater at 188±21 rotations 30 min−1 than those obtained in sham-lesioned rats (4±1 rotations 30 min−1).

Effective loss (99.9±0.1% reduction in lesion compared with the control side; P<0.05) of [3H]-mazindol binding to striatal dopaminergic terminals was observed in

Distribution of GABAB receptor mRNA in the BG and thalamus

All of the GABAB receptor mRNA species examined showed relatively widespread distribution throughout the BG and thalamus. The pattern of gene expression noted for the GABAB(2) subunit was consistent with previous reports, showing a characteristic absence of mRNA within the striatum and NAcb and highest levels within the thalamus Durkin et al., 1999, Clark et al., 2000. The data obtained here are concordant with those of Liang et al. (2000), showing highest levels of GABAB(1a) mRNA expression in

Acknowledgements

This research was funded by the British Pharmacological Society and the Parkinson's Disease Society. T. Johnston was funded by an A. J. Clark Studentship from the British Pharmacological Society.

References (37)

  • P.D. Griffiths et al.

    Changes in benzodiazepine and acetylcholine receptors in the globus pallidus in Parkinson's disease

    J Neurol Sci

    (1990)
  • F. Hefti et al.

    Circling behavior in rats with partial, unilateral nigro-striatal lesionseffect of amphetamine, apomorphine, and DOPA

    Pharmacol Biochem Behav

    (1980)
  • S. Isomoto et al.

    Cloning and tissue distribution of novel splice variants of the rat GABAB receptor

    Biochem Biophys Res Commun

    (1998)
  • R.G. Robertson et al.

    The role of striatopallidal neurones utilizing gamma-aminobutyric acid in the pathophysiology of MPTP-induced parkinsonism in the primateevidence from [3H]flunitrazepam autoradiography

    Brain Res

    (1990)
  • K.Z. Shen et al.

    Presynaptic GABAB receptors inhibit synaptic inputs to rat subthalamic neurons

    Neuroscience

    (2001)
  • H. Bergman et al.

    The primate subthalamic nucleusII. Neuronal activity in the MPTP model of parkinsonism

    J Neurophysiol

    (1994)
  • A. Billinton et al.

    GABAB receptor isoforms GBR1a and GBR1b, appear to be associated with pre- and post-synaptic elements respectively in rat and human cerebellum

    Br J Pharmacol

    (1999)
  • S. Bischoff et al.

    Spatial distribution of GABABR1 receptor mRNA and binding sites in the rat brain

    J Comp Neurol

    (1999)
  • Cited by (25)

    • Blockade of pre-synaptic and post-synaptic GABA<inf>B</inf> receptors in the lateral habenula produces different effects on anxiety-like behaviors in 6-hydroxydopamine hemiparkinsonian rats

      2021, Neuropharmacology
      Citation Excerpt :

      Pre-synaptic GABAB receptors inhibit release of GABA and other neurotransmitters, while post-synaptic GABAB receptors may decrease neuronal excitability (Bowery et al., 2002; Ulrich and Bettler, 2007). In parkinsonian animals, studies have found changes in GABAB receptor-mediated inhibitory transmission, with evidence including increased activity of glutamic acid decarboxylase (GAD, the GABA-synthesizing enzyme; Soghomonian and Chesselet, 1992; Pedneault and Soghomonian, 1994; Soghomonian and Laprade, 1997), GABA release (Kish et al., 1986; Galeffi et al., 2003; Emir et al., 2012), reduced GABA re-uptake by GABA transporter (GTA; Chazalon et al., 2018) and altered GABAB receptor binding and expression of GABAB receptor subunits in the basal ganglia and thalamus (de Groote et al., 1999; Calon et al., 2000; Johnston and Duty, 2003). Further, several studies from our laboratory have found the 6-OHDA lesions of the substantia nigra pars compacta (SNc) in rats decrease synthesis and release of GABA, enhance re-uptake of GABA and increase release of glutamate in the LHb, which lead to the hyperactivity of LHb neurons (Wang et al., 2017; Hui et al., 2020; Lyu et al., 2020).

    • Ketogenic diet prevents neuronal firing increase within the substantia nigra during pentylenetetrazole-induced seizure in rats

      2016, Brain Research Bulletin
      Citation Excerpt :

      Such a decrease in reactivity of SNr due to KD does not contradict the anti-seizure role of the GABAergic SNr-neurons, because the anti-seizure effect of KD, as evaluated in the present work, arises from a prolonged treatment. In fact, it can be argued that a prolonged decrease in the firing rate of GABAergic neurons due to KD (Ma et al., 2007) could induce an increased sensibility of nigrostriatal targets to GABA; this possibility is supported by the evidence that a lesion of the nigrostriatal pathway, which produces a decrease in GABA inputs to the nigrostriatal targets, is followed by an up-regulation of GABA(B) receptors in those targets (Johnston and Duty, 2003). In addition to hypotheses of neural plasticity, other hypotheses should also be taken into account.

    • Neuronal firing activity and gene expression changes in the subthalamic nucleus after transplantation of dopamine neurons in hemiparkinsonian rats

      2013, Neurobiology of Disease
      Citation Excerpt :

      The STN receives GABAergic afferences from the GPe. Based on previous in situ hybridization studies of GABA receptor subunits (Johnston and Duty, 2003; Wisden et al., 1992), we selected three GABAA subunits α1, β2, and γ2 (Gabra1, Gabrb2, Gabrg2) and one GABAB subunit 1 (Gabbr1). No differences were observed in any of those four GABA receptor genes (Fig. 6B).

    • Therapeutic potential of GABA<inf>B</inf> receptor ligands in drug addiction, anxiety, depression and other CNS disorders

      2013, Pharmacology Biochemistry and Behavior
      Citation Excerpt :

      It has also been reported that changes in the function or localization of GABAB receptors and GABAergic transmission in external and internal segments of the GP (GPe and GPi), contribute to the pathophysiology of the basal ganglia network in PD (Galvana et al., 2011). In PD patients and in experimental animal models, the levels of protein or mRNA for GABAB receptors were found to be lower than normal in GPe and up-regulated in GPi (Calon et al., 2000; Johnston and Duty, 2003). The therapeutic potential was also investigated in experimentally in α-Synuclein transgenic model systems.

    View all citing articles on Scopus
    View full text