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  • Contrary to the profuse dopaminergic innervation of the thal

    2019-07-10

    Contrary to the profuse dopaminergic innervation of the thalamus found in human and non-human primates (Brown et al., 1979, Sanchez-Gonzalez et al., 2005), in rodents, the RTn is one the few thalamic nuclei that receives dopaminergic input (Anaya-Martinez et al., 2006, Garcia-Cabezas et al., 2007, Garcia-Cabezas et al., 2009). In line with this, the presence of D4-type receptors in the RTn of primates (Mrzljak et al., 1996b) and rodents (Erlij et al., 2012, Gasca-Martinez et al., 2010, Govindaiah et al., 2010) is well established. There is evidence of Globus pallidus (GP, equivalent to external Globus pallidus in primates, GPe) GABAergic projections fibers to the RTn in primates (Asanuma, 1994, Hazrati and Parent, 1991), felines (Kayahara and Nakano, 1998) and rodents (Asanuma and Porter, 1990, Cornwall et al., 1990, Gandia et al., 1993). Furthermore, intracellular recordings from RTn neurons indicate that these pallido-RTn terminals express D4-type receptors that, when activated, reduce the amplitude of GABAergic postsynaptic inhibitory potentials (Gasca-Martinez et al., 2010, Govindaiah et al., 2010). In addition, support for these data comes from reports of the Dp44mT weight of D4-type receptors in GP neurons (Ariano et al., 1997) and from studies demonstrating that activation of D4-type receptors reduce GABA release in the RTn (Floran et al., 2004). Moreover, RTn and dopamine D4-type receptors are associated with another\'s pathologies of the central nervous system, for example: multidisciplinary data suggests that a subcortical hyperdopaminergic condition is the key factor in the emergence of schizophrenia (Brisch et al., 2014, Durstewitz and Seamans, 2008, Gründer and Cumming, 2016). In addition, the electrical activity of RTn neurons is abnormal in schizophrenics and in animal models of schizophrenia (Ferrarelli et al., 2010, Ferrarelli and Tononi, 2011, Pinault, 2011, Pratt and Morris, 2015, Troyano-Rodriguez et al., 2014). Moreover, atypical antipsychotics, through their high affinity for D4-type dopamine receptors, are successfully used for the clinical treatment of schizophrenia (Lindsley and Hopkins, 2017, Naheed and Green, 2001). This conceptual framework and background pointed us to the need of analyzing the role of D4-type dopamine receptors in the RTn. Here we study the effects of the local activation and blockade of D4-type dopamine receptors in RTn neurons of rats under normal conditions and with ipsilateral destruction of the dopaminergic system. Our data provides evidence of the crucial role that D4-type dopamine receptors plays in the global electrical activity of RTn neurons. It is, to our knowledge, the first study that describes the role of dopamine in the in vivo spiking activity of RTn neurons in a rat model of Parkinson’s disease.
    Materials and methods
    Main Text In the striatum, dopamine release shapes reward-seeking behavior and motor control, and its dysregulation is implicated in disorders ranging from addiction to schizophrenia (Graybiel and Mink, 2009). Two distinct populations of midbrain neurons release dopamine into the striatum: the dorsal striatum (DStr) receives dopaminergic inputs predominately from the substantia nigra (SNc) and the ventral striatum/nucleus accumbens (NAc) from the ventral tegmental area (VTA). Along with different afferents, the striatal subdivisions diverge in their efferent connectivity and are thus positioned to influence diverse behaviors. Dopamine release is also differentially regulated in the striatal compartments, but how these differences are captured by dopamine receptors on striatal projection neurons is unknown. To dissect disease mechanisms associated with dopaminergic dysregulation, we must first determine how dopamine acts on its receptors in specific striatal subdivisions. In this issue of Neuron, Marcott et al. (2018) tackle this question by exploring how dopamine signaling is encoded by D2 receptors (D2Rs) in striatal medium spiny neurons (MSNs). They first confirm that dopamine concentrations are differently regulated in striatal subregions with fast-scan cyclic voltammetry. Like prior reports, dopamine release and uptake are greater in DStr than NAc (Figure 1A). To examine how differences in release are encoded, Marcott et al. (2018) use a trick, by overexpressing a G-protein-coupled inward-rectifying potassium (GIRK) channel to measure D2R activation. Normally, GIRK2 acts downstream of Gi/o-coupled receptors, including D2R. This clever approach allows potassium conductance to be used as a receptor activation sensor, measured as D2R-mediated inhibitory postsynaptic currents (D2-IPSCs). Marcott et al. (2018) first confirm that GIRK2-overexpression-mediated D2-IPSCs occur exclusively in D2-MSNs, consistent with the inability of GIRK to signal with Gs-coupled receptors, including D1R. In a series of elegant whole-cell voltage-clamp recordings, Marcott et al. (2018) use this sensor to show that NAc D2Rs activate and decay more slowly than DStr D2Rs despite similar dopamine release kinetics between NAc and DStr (Figure 1A).