Enhancement of excitatory synaptic integration by GABAergic inhibition in the subthalamic nucleus

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-v channel 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 beta-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 beta-oscillations between the cortex and STN in PD.