GABAergic control of the subthalamic nucleus
Introduction
The subthalamic nucleus (STN) is a lens-shaped structure that rests on the internal capsule. In terms of its dimensions and total number of neurons, the STN is a relatively minor component of the basal ganglia (Oorschot, 1996). However, in functional terms, the STN is considerably more significant because abnormal activity of the STN is associated with profound disorders of movement and direct manipulation of the STN can ameliorate the symptoms of such disorders (Bergman et al., 1994; Wichmann et al., 1994). Twenty years ago Kita and Kitai termed the STN the ‘driving force’ of the basal ganglia because it is predominantly composed of glutamatergic projection neurons that innervate the GABAergic external segment of the globus pallidus (GPe in primates, GP in subprimates) and the basal ganglia output nuclei (the internal segment of the globus pallidus (GPi) and the substantia nigra (SN) (Nakanishi et al., 1987a; Smith and Parent, 1988; Bevan et al., 1994). In accordance with their proposition (which at the time was controversial), the STN has since been shown to drive, in part, the resting tonic activity of the basal ganglia and in addition, relay phasic cortical and thalamic excitation to its target nuclei during movement (Fujimoto and Kita, 1993; Maurice et al., 1998). The output of the STN is however precisely regulated by powerful feedback inhibition from the reciprocally connected GABAergic GPe/GP (Shink et al., 1996). Although key to understanding both the normal and pathological operation of the basal ganglia, the interaction between the STN and GPe has been difficult to incorporate into models of basal ganglia function and dysfunction, in part, because the interaction between the STN and GPe/GP neurons is complicated by their intrinsic membrane properties, which underlie unusual forms of synaptic integration (Bevan et al., 2002; Hanson et al., 2004; Baufreton et al., 2005a; Hallworth and Bevan, 2005).
Recent studies have demonstrated strong correlations between the patterns of STN activity and the symptoms of Parkinson's disease. Together with the discovery of direct dopaminergic inputs to the STN that degenerate in Parkinson's disease (PD) (Lavoie et al., 1989; Hassani et al., 1997; Francois et al., 2000; Cragg et al., 2004), there is speculation that abnormal activity in PD may be due, partly, to the loss of dopamine in the STN and abnormal patterning of the STN by GABAergic inputs from the GPe (Hallworth and Bevan, 2005; Baufreton et al., 2005a).
The primary objective of this chapter is to review the principles underlying the patterning of STN activity by GABAergic inhibition arising from the GPe/GP under normal conditions and in the absence of dopamine. The following subjects will be reviewed: the major inputs to STN neurons; the intrinsic membrane properties of STN neurons; the principles underlying inhibitory synaptic integration; the influence of GABAergic inhibition on the integration of glutamatergic synaptic inputs; the regulation by dopamine of GABAergic inhibition in the STN; and finally the patterning of STN activity by GABAergic inhibition in vivo.
Section snippets
GABAergic afferents of the STN
The major GABAergic input to the STN is derived from the GPe/GP. The projection is ipsilateral and topographic in nature (Smith et al., 1990; Shink et al., 1996; Bevan et al., 1997) and largely reciprocated by an excitatory projection from the STN (Shink et al., 1996). Although similar functional (motor, associative and limbic) zones are reciprocally connected, a certain degree of divergence/overlap exists between functionally divergent neurons (Bevan et al., 1997; Joel and Weiner, 1997).
In
Autonomous pacemaker activity
In vitro and in the absence of ionotropic receptor mediated GABAergic and glutamatergic synaptic inputs, STN neurons rhythmically discharge action potentials (APs) at ∼ 5–15 Hz (Fig. 3A; Bevan and Wilson, 1999; Beurrier et al., 2000; Do and Bean, 2003). This activity is driven by voltage-dependent Na+ (Nav) channels, which underlie subthreshold persistent and resurgent currents. The period and precision of autonomous activity is determined by small conductance Ca2+-dependent K+ (SK) channels,
Types of GABAR in the STN
STN neurons express the most common combination of GABAAR subunits in the brain i.e., α1, β2/3, γ2 (Wisden et al., 1992). In accordance with this molecular composition, barbiturates and benzodiazepines enhance both the magnitude and duration of spontaneous IPSCs in STN neurons (Baufreton et al., 2001). Because benzodiazepines can enhance the amplitude of spontaneous IPSCs, synaptic GABAARs do not appear to be saturated during low-frequency synaptic transmission (Perrais and Ropert, 1999).
GABAAR
Deinactivation of Nav channels by IPSPs
Following single or multiple low-frequency GABAAR-mediated IPSPs, the autonomous activity of STN neurons may resume in the absence of rebound burst firing (Bevan et al., 2002; Hallworth and Bevan, 2005; Baufreton et al., 2005a). However, close inspection of APs reveals that they are briefly modified after inhibition: threshold is lowered and the maximal rate of the rise of voltage is increased (Fig. 7A; Baufreton et al., 2005a). These observations suggest that Nav channel availability is
Activity-dependent synaptic plasticity/cellular excitability
In accordance with its actions in other brain regions, dopamine predominantly influences synaptic transmission in the STN through the activation of presynaptic D2-like receptors, which lower the initial probability of neurotransmitter release at GABAergic and glutamatergic synapses (Shen and Johnson, 2000). The action on GABAergic transmission is more potent than the effect on glutamatergic transmission. By reducing the initial release probability, depression due to vesicle depletion and/or
Patterning of STN activity in vivo: proven and potential roles for GABAergic inhibition
Multiple studies provide evidence for a pivotal role of the GPe/GP in patterning the activity of the STN in vivo. Brief motor cortical stimulation in vivo (that is meant to approximate a descending motor command) generates a stereotyped triphasic sequence of activity in STN neurons (Fujimoto and Kita, 1993; Maurice et al., 1998; Magill et al., 2004). The first response is excitatory and is mediated by the direct cortico-subthalamic pathway. In rodents it occurs with a latency of ∼4–7 ms and
Acknowledgements
Our work is supported by NIH-NINDS Grants NS041280 (MDB) and NS040705 (MDB), the National Parkinson Foundation (NEH) and L’Association France Parkinson (JB).
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