Subthalamic nucleus lesions: widespread effects on changes in gene expression induced by nigrostriatal dopamine depletion in rats

Delfs, Jill M.; Ciaramitaro, VM; Parry, T. Wilson; Chesselet, M.-F.

doi:10.1523/jneurosci.15-10-06562.1995

Cited by 92 publications

(56 citation statements)

References 76 publications

(98 reference statements)

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“…12,23,24 According to previous studies, 6-OHDA lesioning in rat parkinsonian models induced hyperactivity of the PPN, SNpr, and STN neurons, as compared Effect of enhanced GAD65 expression in a rat parkinsonian model B Lee et al to normal control rats. 12,25 Our present results indicate that, compared with the PD rats, the group of rats injected with the GAD65-containing JDK-driven vector exhibited more constant improvement in firing rates than did the group of the rats injected with the CMV-driven vector.…”

Section: Discussionmentioning

confidence: 98%

Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models

Lee

Nam

et al. 2005

Gene Ther

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In this study, we report the amelioration of parkinsonian symptoms in rat Parkinson's disease (PD) models, as a result of the expression of glutamate decarboxylase (GAD) 65 with a modified cytomegalovirus (CMV) promoter. The transfer of the gene for gamma-amino butryic acid (GAD), the rate-limiting enzyme in gama-amino butrylic acid (GABA) production, has been investigated as a means to increase inhibitory synaptic activity. Electrophysiological evidence suggests that the transfer of the GAD65 gene to the subthalamic nucleus (STN) can change the excitatory output of this nucleus to inhibitory output. Our in vitro results also demonstrated higher GAD65 expression in cells transfected with the JDK promoter, as compared to cells transfected with the CMV promoter. Also, a rat PD model in which recombinant adeno-associated virus-2 (rAAV2)-JDK-GAD65 was delivered into the STN exhibited significant behavioral improvements, as compared to the saline-injected group. Interestingly, we observed that these behavioral improvements were more obvious in rat PD models in which rAAV2-JDK-GAD65 was injected into the STN than in rat PD models in which rAAV2-CMV-GAD65 was injected into the STN. Moreover, according to electrophysiological data, the rAAV2-JDK-GAD65-injected group exhibited more constant improvements in firing rates than did the rAAV2-CMV-GAD65-injected group. These data indicate that the JDK promoter, when coupled with GAD65 expression, is more effective with regard to parkinsonian symptoms than is the CMV promoter.

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Section: Discussionmentioning

confidence: 98%

Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models

Lee

Nam

et al. 2005

Gene Ther

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“…Moreover, the activity of STN neurons was observed to be enhanced after lesion of the external globus pallidus ; but see Hassani et al, 1996). On the other hand, some aspects of pallidal neuronal activity seem to be augmented under conditions of chronic dopamine depletion; neuronal bursting activity is increased (Pan and Walters, 1988), and levels of mRNA for the GABAergic metabolic enzyme GAD67 are elevated (K incaid et al, 1992;Soghomonian and Chesselet, 1992;Delfs et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…The enhanced activity of these output structures in the dopamine-depleted state may be due, in part, to an elevation of the excitatory drive from the subthalamic nucleus (STN) (Miller and DeL ong, 1987). In accordance with this hypothesis, procedures thought to reduce subthalamic neuronal output have been found to reverse the behavioral effects of dopamine depletion in rats (Anderson et al, 1992;Blandini et al, 1995;Delfs et al, 1995), primates (Bergman et al, 1990;Aziz et al, 1991;Benazzouz et al, 1993), and humans (Benabid et al, 1994;Limousin et al, 1995;Pollak et al, 1996).…”

Section: Analysis; Firing Patternmentioning

confidence: 95%

The Response of Subthalamic Nucleus Neurons to Dopamine Receptor Stimulation in a Rodent Model of Parkinson’s Disease

et al. 1997

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Overactivity in the subthalamic nucleus (STN) is believed to contribute to the pathophysiology of Parkinson's disease. It is hypothesized that dopamine receptor agonists reduce neuronal output from the STN. The present study tests this hypothesis by using in vivo extracellular single unit recording techniques to measure neuronal activity in the STN of rats with 6-hydroxydopamineinduced lesions of the nigrostriatal pathway (a model of Parkinson's disease). As predicted, firing rates of STN neurons in lesioned rats were tonically elevated under basal conditions and were decreased by the nonselective dopamine receptor agonists apomorphine and L-3,4-dihydroxyphenylalanine (L-DOPA). STN firing rates were also decreased by the D2 receptor agonist quinpirole when administered after the D1 receptor agonist (Ϯ)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393). Results of the present study challenge the prediction that dopaminergic agonists reduce STN activity predominantly through actions at striatal dopamine D2 receptors. Firing rates of STN neurons were not altered by selective stimulation of D2 receptors and were increased by selective stimulation of D1 receptors. Moreover, there was a striking difference between the responses of the STN to D1/D2 receptor stimulation in the lesioned and intact rat; apomorphine inhibited STN firing in the lesioned rat and increased STN firing in the intact rat. These findings support the premise that therapeutic efficacy in the treatment of Parkinson's disease is associated with a decrease in the activity of the STN, but challenge assumptions about the roles of D1 and D2 receptors in the regulation of neuronal activity of the STN in both the intact and dopamine-depleted states.

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“…After injection, the syringe was left in place for 5 min and then slowly withdrawn. Animals were allowed to recover for 8 d. To select animals with appropriate lesions, animals were challenged with apomorphine (0.5 mg/kg, s.c.) on day 9 to test for ipsilateral rotational behavior (Delfs et al, 1995). Animals demonstrating Ͼ10 ipsilateral rotations/5 min were used in this experiment.…”

Section: Drugsmentioning

confidence: 99%

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study

1997

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Metabotropic glutamate receptors (mGluRs) are a major class of excitatory amino acid receptors. Eight mGluR subtypes, coupled to a variety of effector systems, have been cloned. These receptors have been classified into three groups based on amino acid sequence homology, effector systems, and pharmacological profile. Group I mGluRs increase phosphoinositide turnover, whereas groups II and III mGluRs are negatively coupled to adenylyl cyclase. The striatum possesses a high density of mGluR binding sites, and several mGluR mRNAs and proteins are expressed by striatal neurons. In rats, unilateral striatal injection of the nonsubtype selective mGluR agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) results in contralateral rotation with delayed onset, thought to be secondary to an increase in dopamine release. We sought to determine the mGluR subtype(s) involved, the modulation of the rotation by other basal ganglia neurotransmitter systems, and the functional anatomy underlying the rotational behavior. The group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) induced contralateral rotation in a dose-dependent manner, whereas group II and group III agonists were ineffective. Rotation induced by DHPG or 1S,3R-ACPD was attenuated by group I antagonists, but not by group II or group III antagonists. This suggests that the rotation is mediated by group I mGluRs. Rotation induced by DHPG or 1S,3R-ACPD was attenuated by pretreatment with antagonists at muscarinic cholinergic, adenosine A 2 , dopamine D 2 , or dopamine D 1 receptors. Examination of FOS-like immunoreactivity after group I and group II mGluR agonist administration suggests increased activity in the striatopallidal pathway. However, [ 14 C]-2-deoxyglucose uptake studies indicate increased activity in nuclei of the striatopallidal (indirect) pathway, particularly in the subthalamic nucleus, only after group I mGluR activation. Key words: metabotropic glutamate receptor; basal ganglia; subthalamic nucleus; striatum; dopamine; adenosine A2 receptors; muscarinic receptorsExcitatory amino acids (EAAs) are important neurotransmitters in the basal ganglia, and EAAergic agents are being investigated actively as possible pharmacotherapies for basal ganglia disorders. A major class of EAA receptors are the metabotropic glutamate receptors (mGluRs), coupled to second messenger systems via G-proteins. Eight mGluR subtypes have been cloned, several of which possess splice variants. These mGluR subtypes have been categorized into three groups based on their amino acid sequence homology, effector systems, and pharmacological profile. When expressed and activated in transfection systems, group I receptors (mGluRs 1 and 5) stimulate phosphoinositide hydrolysis. Group II (mGluRs 2 and 3) and group III (mGluRs 4 -8) receptors inhibit adenylyl cyclase, although with different pharmacological profiles (for review, see Pin and Duvosin, 1995;Roberts, 1995). Ligand-binding studies have shown the striatum to possess a high density of mGluR binding sites (Albin et al....

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Subthalamic nucleus lesions: widespread effects on changes in gene expression induced by nigrostriatal dopamine depletion in rats

Cited by 92 publications

References 76 publications

Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models

Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models

The Response of Subthalamic Nucleus Neurons to Dopamine Receptor Stimulation in a Rodent Model of Parkinson’s Disease

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study

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Subthalamic nucleus lesions: widespread effects on changes in gene expression induced by nigrostriatal dopamine depletion in rats

Cited by 92 publications

References 76 publications

Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models

Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models

The Response of Subthalamic Nucleus Neurons to Dopamine Receptor Stimulation in a Rodent Model of Parkinson’s Disease

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [14C]-2-Deoxyglucose Autoradiographic Study

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Product

Resources

About

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study