Abstract
The globus pallidus (GP) is emerging as a critical locus of basal ganglia control of motor activity, but the exact role of GABAergic GP neurons remain to be defined. By targeted expression of channelrhodopsin 2 (ChR2) in GABAergic neurons using the VGAT-ChR2-EYFP transgenic mice, we showed that optogenetic stimulation of GABAergic neurons in the right GP produced hyperkinesia. Optogenetic stimulation of GABAergic GP neurons increased c-Fos-positive cells in GP, M1 cortex, and caudate-putamen (CPu), and decreased c-Fos-positive cells in entopeduncular nucleus (EPN), compared to the contralateral hemisphere. In agreement with the canonical basal ganglia model. Furthermore, we delivered AAV-CaMKIIα-ChR2-mCherry virus to the excitatory neurons of the subthalamic nucleus (STN) and selectively stimulated glutamatergic afferent fibers from the STN onto the GP. This optogenetic stimulation produced abnormal movements, similar to the behaviors that observed in the VGAT-ChR2-EYFP transgenic mice. Meanwhile, we found that the c-Fos expression pattern in the GP, M1, STN, EPN, and CPu produced by optogenetic activation of glutamatergic afferent fibers from the STN in GP was similar to the c-Fos expression pattern in the VGAT-ChR2-EYFP transgenic mice. Taken together, our results suggest that excess GP GABAergic neurons activity could be the neural substrate of abnormal involuntary movements in hyperkinetic movement disorders. The neural circuitry underlying the abnormal involuntary movements is associated with excessive GP, M1, CPu activity, and reduced EPN activity. Inhibition of GP GABAergic neurons represents new treatment targets for hyperkinetic movement disorder.
Highlights
The basal ganglia (BG), consisting of the striatum; the internal and external globus pallidus (GPi and GPe), which are referred to as the globus pallidus (GP) and the entopeduncular nucleus (EPN) in rodents; the subthalamic nucleus (STN) and the substantianigra (SN), receives and processes cortical inputs and in return regulates cortical activity (Albin et al, 1989)
We first verified that channelrhodopsin 2 (ChR2) expression was restricted to GABAergic neurons under control of vesicular GABA transporter (VGAT) promoter, which directed the selective expression of ChR2 in GABAergic and glycinergic neurons (Chaudhry et al, 1998) in the VGAT-ChR2EYFP transgenic mice (Zhao et al, 2011)
We found that ChR2 stimulation of glutamatergic afferent fibers from the STN in the GP increased the c-Fos-positive neurons in the ipsilateral GP, M1, and CPu, and decreased the c-Fos-positive neurons in the ipsilateral EPN, compared to the contralateral side, similar to the ChR2 stimulation of GP GABAergic neurons in the VGAT-ChR2-EYFP transgenic mice
Summary
The basal ganglia (BG), consisting of the striatum; the internal and external globus pallidus (GPi and GPe), which are referred to as the globus pallidus (GP) and the entopeduncular nucleus (EPN) in rodents; the subthalamic nucleus (STN) and the substantianigra (SN), receives and processes cortical inputs and in return regulates cortical activity (Albin et al, 1989). The BG plays an important role in motor control through the direct and indirect pathways with the coordinated activity but often opposite effects on movement; the direct pathway selects. Consistent with the classical model of the basal ganglia, optogenetic activation of the striatal media spiny neurons (MSNs) in the direct pathway increases ambulation, while activation of the striatal MSNs in the indirect pathway decreases ambulation (Kravitz et al, 2010). The critical role of the GP in the control of movement is illustrated by the abnormal activity of GP neurons in movement disorders, including the increased firing rates in the GP in Huntington’s disease (Starr et al, 2008) and beta oscillations of the GP neurons in Parkinson’s disease (PD) (Mallet et al, 2008). Consistent with the critical role of the GP in basal ganglia circuits and behavior, quinolinic acid lesion of the GP leads to a decrease in spontaneous movement (Hauber et al, 1998) and activation of GP neurons by the microinjection of the GABAA receptor antagonist bicuculline (Matsumura et al, 1995) into the GP induces spontaneous movement (Grabli et al, 2004) and dyskinesia in primates (Crossman et al, 1984; Bronfeld et al, 2010)
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