Studies in dopamine-depleted rats indicate that the external globus pallidus (GPe) contains two main types of GABAergic projection cell; so-called “prototypic” and “arkypallidal” neurons. Here, we used correlative anatomical and electrophysiological approaches in rats to determine whether and how this dichotomous organization applies to the dopamine-intact GPe. Prototypic neurons coexpressed the transcription factors Nkx2-1 and Lhx6, comprised approximately two-thirds of all GPe neurons, and were the major GPe cell type innervating the subthalamic nucleus (STN). In contrast, arkypallidal neurons expressed the transcription factor FoxP2, constituted just over one-fourth of GPe neurons, and innervated the striatum but not STN. In anesthetized dopamine-intact rats, molecularly identified prototypic neurons fired at relatively high rates and with high regularity, regardless of brain state (slow-wave activity or spontaneous activation). On average, arkypallidal neurons fired at lower rates and regularities than prototypic neurons, and the two cell types could be further distinguished by the temporal coupling of their firing to ongoing cortical oscillations. Complementing the activity differences observedin vivo, the autonomous firing of identified arkypallidal neuronsin vitrowas slower and more variable than that of prototypic neurons, which tallied with arkypallidal neurons displaying lower amplitudes of a “persistent” sodium current important for such pacemaking. Arkypallidal neurons also exhibited weaker driven and rebound firing compared with prototypic neurons. In conclusion, our data support the concept that a dichotomous functional organization, as actioned by arkypallidal and prototypic neurons with specialized molecular, structural, and physiological properties, is fundamental to the operations of the dopamine-intact GPe.

The activity patterns of subthalamic nucleus (STN) neurons, which are intimately related to normal movement and abnormal movement in Parkinson's disease (PD), are sculpted by feedback GABAergic inhibition from the reciprocally connected globus pallidus (GP). To understand the principles underlying the integration of GABAergic inputs, we used gramicidin-based patch-clamp recording of STN neurons in rat brain slices. Voltage-dependent Na⁺(Na_v) channels actively truncated synthetic IPSPs and were required for autonomous activity. In contrast, hyperpolarization-activated cyclic nucleotide-gated and class 3 voltage-dependent Ca²⁺channels contributed minimally to the integration of single or low-frequency trains of IPSPs and autonomous activity. Interestingly, IPSPs modified action potentials (APs) in a manner that suggested IPSPs enhanced postsynaptic Na_vchannel availability. This possibility was confirmed in acutely isolated STN neurons using current-clamp recordings containing IPSPs as voltage-clamp waveforms. Tetrodotoxin-sensitive subthreshold and spike-associated Na⁺currents declined during autonomous spiking but were indeed transiently boosted after IPSPs. A functional consequence of inhibition-dependent augmentation of postsynaptic excitability was that EPSP–AP coupling was dramatically improved when IPSPs preceded EPSPs.Because STN neuronal activity exhibits coherence with cortical β-oscillations in PD, we tested how rhythmic sequences of cortical EPSPs were integrated in the absence and presence of feedback inhibition. STN neuronal activity was consistently entrained by EPSPs only in the presence of feedback inhibition. These observations suggest that feedback inhibition from the GP is critical for the emergence of coherent β-oscillations between the cortex and STN in PD.

The symptoms of Parkinson's disease (PD) are related to changes in the frequency and pattern of activity in the reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN). In idiopathic and experimental PD, the GPe and STN exhibit hypoactivity and hyperactivity, respectively, and abnormal synchronous rhythmic burst firing. Following lesion of midbrain dopamine neurons, abnormal STN activity emerges slowly and intensifies gradually until it stabilizes after 2–3 weeks. Alterations in cellular/network properties may therefore underlie the expression of abnormal firing. Because the GPe powerfully regulates the frequency, pattern, and synchronization of STN activity, electrophysiological, molecular, and anatomical measures of GPe–STN transmission were compared in the STN of control and 6-hydroxydopamine-lesioned rats and mice. Following dopamine depletion: (1) the frequency (but not the amplitude) of mIPSCs increased by ∼70%; (2) the amplitude of evoked IPSCs and isoguvacine-evoked current increased by ∼60% and ∼70%, respectively; (3) mRNA encoding α1, β2, and γ2 GABA_Areceptor subunits increased by 15–30%; (4) the density of postsynaptic gephyrin and γ2 subunit coimmunoreactive structures increased by ∼40%, whereas the density of vesicular GABA transporter and bassoon coimmunoreactive axon terminals was unchanged; and (5) the number of ultrastructurally defined synapses per GPe–STN axon terminal doubled with no alteration in terminal/synapse size or target preference. Thus, loss of dopamine leads, through an increase in the number of synaptic connections per GPe–STN axon terminal, to substantial strengthening of the GPe–STN pathway. This adaptation may oppose hyperactivity but could also contribute to abnormal firing patterns in the parkinsonian STN.