Bidirectional dopamine modulation of excitatory and inhibitory synaptic inputs to subthalamic neuron subsets containing α4β2 or α7 nAChRs

Abstract

The subthalamic nucleus (STN) possesses microcircuits distinguished by subtypes of nicotinic acetylcholine receptors (nAChRs). Although dysfunction of the STN is well-known in Parkinson's disease, there is still little information about whether dopamine differentially modulates excitatory and inhibitory synaptic inputs to STN neurons expressing different nAChR subtypes. To address this issue, we performed brain slice patch-clamp recordings on STN neurons, while we pharmacologically manipulated dopaminergic inputs. In STN neuron subsets containing either α4β2 or α7 nAChRs, D_1 and D_2 receptors respectively enhanced and inhibited spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs) and firing rates. The elevation of dopamine levels resulted in diverse regulations of synaptic transmission in these two neuron subsets, and interestingly, the dopamine regulation of sIPSCs significantly correlated with that of sEPSCs. Surprisingly, depletion of dopamine either by reserpine treatment or by unilateral 6-OHDA lesion of nigrostriatal dopaminergic neurons did not alter synaptic inputs to STN neurons, but STN neurons in the 6-OHDA-lesioned side exhibited hyperactivity. In summary, dopamine regulated both GABAergic and glutamatergic synaptic inputs to STN neuron subsets containing either α4β2 or α7 nAChRs, forming a balancing machinery to control neuronal activity. In parkinsonian mice, postsynaptic mechanisms may exist and contribute to the hyperactivity of STN neurons.