Functional connectivity and integrative properties of globus pallidus neurons

Abstract

The globus pallidus consists of the external (GPe) and the internal (GPi) segments. The GPe and GPi have different functional roles. The GPe is located centrally within multiple basal ganglia feedforward and feedback connections. The GPi is an output nucleus of the basal ganglia. A complex interplay between intrinsic pacemaking conductances and the balance of glutamatergic and GABAergic input largely determines the rate and pattern of firing of pallidal neurons. The initial part of this article introduces recent findings made in vivo that are related to the roles of glutamatergic and GABAergic inputs in the control of pallidal activity. The latter part describes the roles of intrinsic mechanisms of GPe neurons in the integration of the synaptic inputs. The presence of dendritic voltage-gated sodium channels may allow the initiation of dendritic spikes, giving distal inputs on the long and thin GPe dendrites an opportunity to strongly shape spiking activity. Basal ganglia disorders including Parkinson's disease, hemiballismus, and dystonias are accompanied by increased irregularity and synchronized bursts of pallidal activity. These changes may be in part due to changes in the GABA release in the GPe and GPi, but also involve intrinsic cellular changes in pallidal neurons.

Figure 1

A: Diagrams show major synaptic connections form the motor cortex to GPi. B: Diagrams show major synaptic driving forces evoking an early excitation, an inhibition, and a late excitation in GPe and GPi after cortical stimulation. The diagrams are based on the suggestions obtained from previous studies (Nambu et al., 2000, Kita et al., 2004, Kita, 2007, Tachibana et al., 2008). The level of background activity of pallidal and STN neurons are controlled by glutamatergic, GABAergic, and other driving forces including autonomous firing and slow acting neuroactive substances. The motor cortex provides strong inputs to Str and STN. Stimulation of the motor cortex induces a shorter latency excitation in STN than Str. The difference in the excitation latencies in Str and STN produces an early excitation-inhibition sequence in many pallidal neurons. The early excitation in STN evokes an early excitation in GPe and GPi. The Cx-STN-GPe and Cx-Str pathways provide the main sources for the inhibition in STN, GPe, and GPi. The late excitation in STN, which may be due to various mechanisms including the disinhibition from GPe, provides the main source for the late excitation in GPe and GPi.

Figure 2

Rat GPe neuron morphology and location of effective synapses. Effectiveness of synapses was determined in a modeling study by measuring the mutual information between synaptic input at each location and output spikes (Edgerton et al., 2010). When spike initiation was entirely axonal (left), only synapses close to the soma were effective. In contrast, when spike initiation was entirely dendritic (right) only distal synapses were effective. With intermediate dendritic NaV channel densities the locations of effective synapses was more evenly distributed. Adapted from (Edgerton et al., 2010)

Figure 3

Phase response curve (PRC) analysis of GPe neuron synaptic responses. A: An excitatory AMPA-type synaptic input applied at the soma results in an advance of the next spike that depends on the time at which the input is applied. The regular pacemaking spike cycle without input is shown in black. B: By stimulating the neuron with AMPA input at varying times during the spike cycle, the amount of spike advance vs. time of stimulus in spike cycle is plotted to generate the PRC. C: The PRCs for somatic AMPA inputs to our GPe neuron model are shown for 3 different synaptic conductance amplitudes. The dashed line shows the limit that would be reached if the neuron fired a spike immediately after the input. D: The PRCs for distal dendritic input are shown for 3 different AMPA conductance amplitudes. In this case excitatory inputs delivered during the first 2/3rds of the spike cycle result in a delay of the subsequent spike due to SK conductance activation. Adapted from (Schultheiss et al., 2010)