Dopaminergic Modulation of Excitatory Postsynaptic Currents in Rat Neostriatal Neurons

Abstract

Gamma-aminobutyric acid (GABA)-containing medium spiny neurons constitute approximately 90% of the neuronal population in the neostriatum (caudate and putamen) and play an important role in motor programming. Cortical glutamatergic afferents provide the main excitatory drive for these neurons, whereas nigral dopaminergic neurons play a crucial role in regulating their activity. To further investigate the mechanisms underlying the dopaminergic modulation of medium spiny neuronal activity, we tested the effect of dopamine receptor agonists on excitatory synaptic transmission recorded from these neurons. Excitatory postsynaptic currents (EPSCs) were evoked by local stimulation and recorded from medium spiny neurons in postnatal rat striatal thin brain slices. Recordings were made using the whole cell patch-clamp technique under voltage clamp and conditions that selected for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate- and kainate-type glutamate receptor-mediated components of the EPSC. Incubation of slices in 10 microM dopamine resulted in a 33 +/- 11% (mean +/- SE) decrease in the amplitude of evoked EPSCs, an effect that developed during seconds. The relative variability in amplitude of dopamine's effects on medium spiny neuron EPSCs may reflect activation of different receptor subtypes with opposing effects. In contrast to the results with dopamine, incubation of slices in SKF 38393, a D1-type dopamine receptor selective agonist, resulted in dose-dependent potentiation of the medium spiny neuron EPSC that developed during several minutes. At a concentration of 5 microM, SKF 38393 resulted in a 29 +/- 4.5% increase in EPSC amplitude, an effect that was blocked by preincubation with the D1-selective antagonist, SCH 23390 (10 microM). On the other hand, 5 microM SKF 38393 had no apparent effect on medium spiny neuron currents activated by exogenous application of glutamate or kainate. However, because of the inherent limitations of rapid agonist perfusion in the brain slice preparation (caused by slow agonist diffusion and rapid glutamate receptor desensitization) and because of anatomic evidence that colocalizes D1 and glutamate receptors to medium spiny neuron dendrites, our results leave open the possibility that the effect of D1 receptor activation on the EPSC is mediated via modulation of postsynaptic glutamate receptor responsiveness. The significant potentiation by D1 receptor agonists of EPSC amplitude at the cortico-striatal medium spiny synapse that we observed, in part, may underlie the role of D1 receptors in facilitating medium spiny neuronal firing, with implications for understanding regulation of movement.

D1 and D2 Receptor Antagonist Injections in the Prefrontal Cortex Selectively Impair Spatial Learning in Mice

“…Indeed it is interesting to note that administrations of the D1 receptor antagonist induced similar behavioral patterns (ie a selective impairment in the reactivity to the spatial change) when injected into the PFC or the nucleus accumbens. There is now consistent experimental evidence suggesting that striatal glutamate receptor-channels undergo states of phosphorylation and dephosphorylation that can prolong or shorten the time of activation of the channels (Colwell and Levine, 1995;Umemiya and Raymond, 1997) and that these changes are under the control of D1 DA receptors (Chao et al, 2002). Such processes could explain the facilitatory effects of D1 receptors on the short-term processing of spatial information in the two structures.…”

The ability of the mesocortical dopamine system to operate in distinct temporal modes

“…In the same cells, spontaneous firing was decreased for many minutes, similar to what has been reported using extracellular single unit recordings (Au-Young et al 1999). This phenomenon of slowly developing and protracted effects is mimicked by application of DA or its selective receptor agonists in vitro on a variety of ionic currents in PFC neurons and in a variety of preparations (Yang 2000;Umemiya and Raymond 1997;Cameron and Williams 1993;Huang and Kandel 1995;Gribkoff and Ashe 1984;Seamans et al 2001a,b;Trantham-Davidson et al 2004;Seamans and Yang 2004;Gorelova et al 2002;Gorelova and Yang 2000;Chen and Yang 2002;Urban et al 2002;Gonzalez-Burgos et al 2005;Henze et al 2000;Kroener et al 2006;Gorelova et al 2002;Gulledge and Jaffe 2001;Wang and O'Donnell 2001;Fitch et al 2006;Matsuda et al 2006;Yang and Chen 2005;Young and Yang 2005;Yang and Seamans 1996;Floresco et al 2001a,b;Cheer et al 2005). Although the mechanisms that underlie this slow modulation are not entirely clear and it remains possible that eventually a fast acting DA effect will be discovered, given the current state of knowledge, the sluggish and protracted effects of DA appear to represent the predominate mode of action of DA on target neurons in the PFC.…”

Enhanced Striatal NR2B-Containing N-Methyl-d-Aspartate Receptor-Mediated Synaptic Currents in a Mouse Model of Huntington Disease

“…Mice aged 21-31 days were used for all experiments except where mentioned. Acute corticostriatal slices were made as previously described (Joshi and Andrew 2001;Umemiya and Raymond 1997). Briefly, mice were anesthetized with halothane and decapitated, and the brain was rapidly removed into ice-cold, oxygenated (95%O 2 -5%CO 2 ) artificial cerebrospinal fluid (ACSF) that contained (in mM) 125 NaCl, 2.5 KCl, 25 NaHCO 3 , 1.25 NaH 2 PO 4 , 1 MgCl 2 , 2 CaCl 2 , and 25 glucose, titrated to pH 7.3-7.4 with osmolality of 300 -320 mosM.…”

“…The whole cell patch-clamp technique was used to record from single striatal medium-sized spiny neurons (MSNs). MSNs were visualized in situ using a water-immersion objective lens (ACHROPLAN ϫ 40 ϫ) and were identified by location in the caudate or putamen nuclei, as well as by shape and size (ovoid cell body with 8-to 14-m major axis) as described previously (Umemiya and Raymond 1997). Recording electrode resistance was 3-5 M⍀ when filled with solution containing (in mM) 130 Csmethanesulfonate, 5 CsCl, 4 NaCl, 1 MgCl 2 , 5 EGTA, 10 HEPES, 5 lidocaine N-ethyl chloride, 0.5 GTP, 10 Na 2 -phosphocreatine, and 5 MgATP, titrated to pH 7.3 with CsOH and the osmolality was 280 -290 mosM.…”