GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents

Abstract

The external globus pallidus (GP) is a key GABAergic hub in the basal ganglia (BG) circuitry, a neuronal network involved in motor control. In Parkinson's disease (PD), the rate and pattern of activity of GP neurons are profoundly altered and contribute to the motor symptoms of the disease. In rodent models of PD, the striato-pallidal pathway is hyperactive, and extracellular GABA concentrations are abnormally elevated in the GP, supporting the hypothesis of an alteration of neuronal and/or glial clearance of GABA. Here, we discovered the existence of persistent GABAergic tonic inhibition in GP neurons of dopamine-depleted (DD) rodent models. We showed that glial GAT-3 transporters are downregulated while neuronal GAT-1 function remains normal in DD rodents. Finally, we showed that blocking GAT-3 activity in vivo alters the motor coordination of control rodents, suggesting that GABAergic tonic inhibition in the GP contributes to the pathophysiology of PD.

Dysregulation of external globus pallidus‐subthalamic nucleus network dynamics in parkinsonian mice during cortical slow‐wave activity and activation

“…Following the loss of dopamine, increased recruitment of D2-SPNs may contribute. Loss of D2 receptor-mediated regulation of D2-SPN transmission probability is another potential major factor, which could greatly influence the activity-dependent dynamics and thus impact of striatopallidal transmission (Chuhma et al 2011;Miguelez et al 2012;Lemos et al 2016;Chazalon et al 2018). Although non-selective optogenetic stimulation of striatopallidal inputs did not reveal substantial changes in synaptic properties (Miguelez et al 2012), it is not yet clear whether dopamine depletion triggers alterations in D2-SPN inputs to prototypic PV GPe neurons.…”

Dopamine D2-Like Receptors Modulate Intrinsic Properties and Synaptic Transmission of Parvalbumin Interneurons in the Mouse Primary Motor Cortex

“…Data analyses were performed with the Clampfit routine, Origin 7 and a custom-made software for the detection and measurement of sIPSCs and mIPSCs (Detection Mini 8.0, Chazalon et al, 2018). To build the cumulative probability distributions, the same number of events (n=300) has been used for all neurons.…”

Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism

“…To probe the wider potential significance of the regulation of striatal DA by striatal GATs, we explored GAT function in a mouse model of early parkinsonism. A recent study in external globus pallidus of dopaminedepleted rodents found elevated extracellular GABA resulting from downregulation of GAT-3 on astrocytes, mediated through a loss of DA signalling at D2 DA receptors (Chazalon et al, 2018). Conversely, striatal GAT-3 levels are upregulated in mouse models of Huntington's disease (Wójtowicz et al, 2013;Yu et al, 2018).…”

“…Our data provide compelling evidence that GAT function regulates DA output level in the DLS. Dysregulation of GATs in the basal ganglia has now been implicated in several models of neurological disease: in 6-OHDA toxin-based rat and mouse models of dopamine depletion in Parkinson's, astrocytes in the external globus pallidus have downregulated GAT-3 (Chazalon et al, 2018); and in R6/2 and FVB/N transgenic mouse models of Huntington's disease, striatal GAT expression is increased and tonic inhibition by ambient GABA decreased (Cepeda et al, 2013;Wójtowicz et al, 2013;Yu et al, 2018). Given that deficits in DA transmission in DLS, but not in NAcC, are common to transgenic rodent models of parkinsonism prior to cell loss (Janezic et al, 2013;Sloan et al, 2016;Taylor et al, 2014), we explored whether tonic GABAergic inhibition of striatal DA release and its regulation by striatal GATs might be dysregulated in a mouse model of early parkinsonism.…”

“…Furthermore, we found an augmentation of tonic GABA inhibition of DA release in the DLS (and not NAcC), which was accompanied by downregulated GAT-1 and GAT-3 expression. Whether these adaptations in GAT are consequential to reduced dopamine signalling, as occurs in astrocytes in globus pallidus after depletion of dopamine (Chazalon et al, 2018), or to reduced GABA co-release, or to a potential interaction between α-synuclein and striatal GATs and/or astrocytes is not yet known. Regardless, this resulting enhanced tonic inhibition will diminish nigrostriatal DA release, compounding the release deficits underpinned by α-synuclein e.g.…”