Regulation of Inhibitory Synapses by Presynaptic D4 Dopamine Receptors in Thalamus

Govindaiah G, Wang T, Gillette MU, Crandall SR, Cox CL. Regulation of inhibitory synapses by presynaptic D4 dopamine receptors in thalamus. J Neurophysiol 104: 2757–2765, 2010. First published September 8, 2010; doi:10.1152/jn.00361.2010. Dopamine (DA) receptors are the principal targets of drugs used in the treatment of schizophrenia. Among the five DA receptor subtypes, the D4 subtype is of particular interest because of the relatively high affinity of the atypical neuropleptic clozapine for D4 compared with D2 receptors. GABA-containing neurons in the thalamic reticular nucleus (TRN) and globus pallidus (GP) express D4 receptors. TRN neurons receive GABAergic afferents from globus pallidus (GP), substantia nigra pars reticulata (SNr), and basal forebrain as well as neighboring TRN neuron collaterals. In addition, TRN receives dopaminergic innervations from substantia nigra pars compacta (SNc); however, the role of D4 receptors in neuronal signaling at inhibitory synapses is unknown. Using whole cell recordings from in vitro pallido-thalamic slices, we demonstrate that DA selectively suppresses GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) evoked by GP stimulation. The D2-like receptor (D2,3,4) agonist, quinpirole, and selective D4 receptor agonist, PD168077, mimicked the actions of DA. The suppressive actions of DA and its agonists were associated with alterations in paired pulse ratio and a decrease in the frequency of miniature IPSCs, suggesting a presynaptic site of action. GABAA receptor agonist, muscimol, induced postsynaptic currents in TRN neurons were unaltered by DA or quinpirole, consistent with the presynaptic site of action. Finally, DA agonists did not alter intraTRN inhibitory signaling. Our data demonstrate that the activation of presynaptic D4 receptors regulates GABA release from GP efferents but not TRN collaterals. This novel and selective action of D4 receptor activation on GP-mediated inhibition may provide insight to potential functional significance of atypical antipsychotic agents. These findings suggest a potential heightened TRN neuron activity in certain neurological conditions, such as schizophrenia and attention deficit hyperactive disorders.