Receptor subtype-specific modulation by dopamine of glutamatergic responses in striatal medium spiny neurons

Article · February 2003with5 Reads
DOI: 10.1016/S0006-8993(02)03757-5 · Source: PubMed
Abstract
The output of GABAergic medium-sized spiny neurons in the dorsal striatum is controlled in part by glutamatergic input from the neocortex and the thalamus, and dopaminergic input from ventral midbrain. We acutely isolated these neurons from juvenile (P14-24) rats to study the consequences of the interaction between glutamate and dopamine for neuronal excitability. Single-cell RT-PCR analysis was used to identify the expression patterns of dopamine receptors. D1 and D2 dopamine receptor mRNA was detected in 11/22 and 3/22 of isolated neurons, respectively. Receptor mRNA co-expression was detected in 1/22 cells tested. Whole-cell voltage clamp recording (V(h)=-70 mV) was combined with local or bath application of dopaminergic and glutamatergic agonists to explore dopamine receptor modulation of glutamatergic excitation. Glutamate-evoked inward currents (5 microM, Mg(2+)-free, 1 microM glycine) were attenuated by dopamine (5 microM) to 83.2+/-3.6% (n=31). NMDA-evoked (20 microM), APV-sensitive currents were attenuated by dopamine to 80.9+/-4.5% (n=24). NMDA-induced responses were also attenuated by the D1 receptor agonist SKF 38393 (1 microM; n=28), while the D2/3 receptor agonist quinpirole (10 microM) had no effect. The currents evoked by application of AMPA (5 microM) displayed a steady rundown. Application of dopamine abolished or significantly reduced the rundown in the cells tested (n=17). A similar effect was observed after the application of SKF 38393 (1 microM), while quinpirole (10 microM) had no significant effect. Our results provide direct evidence for modulation by dopamine of glutamatergic responses of striatal medium spiny neurons, and demonstrate that the effects of this neuromodulator are receptor subtype specific. Disruption of this modulatory effect is likely to contribute to movement disorders associated with Parkinson's disease.
    • Several studies have shown that D 1 receptors have extensive functional interactions with NMDA receptor and the larger inhibition of the NMDA receptormediated EPSC could be the results of these interactions. This proposal is consistent with the findings that dopamine D 1 receptors modulated NMDA receptor-mediated EPSCs through direct protein-protein interactions in cultured striatal and hippocampal neurons [24,39]. It was found that two regions in the D 1 receptor carboxyl tail are directly and selectively coupled to NMDA glutamate receptor subunits NR1-1a and NR2A and that through these interactions, D1 receptor agonists could selectively inhibit NMDA receptor-mediated currents through a PKA/PKC independent pathway [24].
    [Show abstract] [Hide abstract] ABSTRACT: Nucleus accumbens (nAcb), a major site of action of drugs of abuse and dopamine (DA) signalling in MSNs (medium spiny neurons), is critically involved in mediating behavioural responses of drug addiction. Most studies have evaluated the effects of DA on MSN firing properties but thus far, the effects of DA on a cellular circuit involving glutamatergic afferents to the nAcb have remained rather elusive. In this study we attempted to characterize the effects of dopamine (DA) on evoked glutamatergic excitatory postsynaptic currents (EPSCs) in nAcb medium spiny (MS) neurons in 1 to 21 day-old rat pups. The EPSCs evoked by local nAcb stimuli displayed both AMPA/KA and NMDA receptor-mediated components. The addition of DA to the superfusing medium produced a marked decrease of both components of the EPSCs that did not change during the postnatal period studied. Pharmacologically isolated AMPA/KA receptor-mediated response was inhibited on average by 40% whereas the isolated NMDA receptor-mediated EPSC was decreased by 90%. The effect of DA on evoked EPSCs were mimicked by the D1-like receptor agonist SKF 38393 and antagonized by the D1-like receptor antagonist SCH 23390 whereas D2-like receptor agonist or antagonist respectively failed to mimic or to block the action of DA. DA did not change the membrane input conductance of MS neurons or the characteristics of EPSCs produced by the local administration of glutamate in the presence of tetrodotoxin. In contrast, DA altered the paired-pulse ratio of evoked EPSCs. The present results show that the activation D1-like dopaminergic receptors modulate glutamatergic neurotransmission by preferentially inhibiting NMDA receptor-mediated EPSC through presynaptic mechanisms.
    Full-text · Article · May 2014
    • Consistent with this, D1 receptors acting through PKA increase surface AMPA receptors in neuronal cultures prepared from nucleus accumbens (Sun et al., 2008) and PFC (Sun et al., 2005), whereas D2 receptor agonists decrease surface AMPA receptor levels (Sun et al., 2005). Moreover, membrane currents and potentials evoked by local application of AMPA receptor agonists in striatal and cortical neurons are depressed by D2 receptor stimulation (André et al., 2010 ; Herná Echeagaray et al., 2004; Levine et al., 1996a) and are either unaffected (Calabresi et al., 1995; Seamans et al., 2001a; Zheng et al., 1999) or potentiated (André et al., 2010; Levine et al., 1996a; Lin et al., 2003; Yan et al., 1999) by D1 receptor agonists. Importantly, DA receptor signaling is not sufficient to recruit AMPA receptors to postsynaptic terminals (Sun et al., 2005Sun et al., , 2008), probably because AMPA receptor surface expression and synaptic targeting by lateral diffusion constitute two independent and separately regulated trafficking steps (Shepherd and Huganir, 2007).
    [Show abstract] [Hide abstract] ABSTRACT: Among the many neuromodulators used by the mammalian brain to regulate circuit function and plasticity, dopamine (DA) stands out as one of the most behaviorally powerful. Perturbations of DA signaling are implicated in the pathogenesis or exploited in the treatment of many neuropsychiatric diseases, including Parkinson's disease (PD), addiction, schizophrenia, obsessive compulsive disorder, and Tourette's syndrome. Although the precise mechanisms employed by DA to exert its control over behavior are not fully understood, DA is known to regulate many electrical and biochemical aspects of neuronal function including excitability, synaptic transmission, integration and plasticity, protein trafficking, and gene transcription. In this Review, we discuss the actions of DA on ionic and synaptic signaling in neurons of the prefrontal cortex and striatum, brain areas in which dopaminergic dysfunction is thought to be central to disease.
    Article · Oct 2012
    • Activation of D2Rs also produced a consistent effect, which was a reduction in NMDA and AMPA currents in all D2 cells. Our results differ from those of studies reporting only a decreasing effect or no effect of DA or its agonists on NMDA currents (Calabresi et al., 1995; Nicola & Malenka, 1998; Lin et al., 2003). Besides methodological differences (), it is possible that those studies failed to observe enhancement of NMDA currents because a mixed population of MSSNs was examined.
    [Show abstract] [Hide abstract] ABSTRACT: Striatal medium-sized spiny neurons (MSSNs) receive glutamatergic inputs modulated presynaptically and postsynaptically by dopamine. Mice expressing the gene for enhanced green fluorescent protein as a reporter gene to identify MSSNs containing D1 or D2 receptor subtypes were used to examine dopamine modulation of spontaneous excitatory postsynaptic currents (sEPSCs) in slices and postsynaptic N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents in acutely isolated cells. The results demonstrated dopamine receptor-specific modulation of sEPSCs. Dopamine and D1 agonists increased sEPSC frequency in D1 receptor-expressing MSSNs (D1 cells), whereas dopamine and D2 agonists decreased sEPSC frequency in D2 receptor-expressing MSSNs (D2 cells). These effects were fully (D1 cells) or partially (D2 cells) mediated through retrograde signaling via endocannabinoids. A cannabinoid 1 receptor (CB1R) agonist and a blocker of anandamide transporter prevented the D1 receptor-mediated increase in sEPSC frequency in D1 cells, whereas a CB1R antagonist partially blocked the decrease in sEPSC frequency in D2 cells. At the postsynaptic level, low concentrations of a D1 receptor agonist consistently increased NMDA and AMPA currents in acutely isolated D1 cells, whereas a D2 receptor agonist decreased these currents in acutely isolated D2 cells. These results show that both glutamate release and postsynaptic excitatory currents are regulated in opposite directions by activation of D1 or D2 receptors. The direction of this regulation is also specific to D1 and D2 cells. We suggest that activation of postsynaptic dopamine receptors controls endocannabinoid mobilization, acting on presynaptic CB1Rs, thus modulating glutamate release differently in glutamate terminals projecting to D1 and D2 cells.
    Article · Jan 2010
    • Regulation of striatal GLU transmission can be achieved at different compartments. Medium-sized spiny GABAergic neurons express both dopaminergic (D1 and D2) and glutamatergic (NMDA and AMPA) receptors as shown by single-cell reverse transcription (RT) PCR and physiological stimulations (Lin et al. 2007). Dopamine D2 receptors localized in presynaptic cortico-striatal GLU terminals take part in DA-mediated GLU release and are putatively involved in dampening striatal excitation (Bamford et al. 2004).
    [Show abstract] [Hide abstract] ABSTRACT: Dopamine and L: -glutamate are important signals which guide the development of functional neural circuits within the striatal complex. Disequilibrium of these neurotransmitter systems is believed to be etiological for the genesis of neurological and psychiatric diseases. Since dopamine plays a crucial role for the early transmitter-regulated differentiation of striatal GABAergic neurons, we emphasized that dopaminergic transmission may also be involved in the fine tuning of intra-striatal glutamate action. In this study, we report that dopamine decreases the expression of the glutamate transporter GLT1 but not GLAST in striatal astrocytes by measuring gene and protein expression. Using glutamate-uptake approaches, we demonstrate an increase in glutamate clearance of externally added glutamate in dopamine-treated cultures compared to controls. Our findings imply that dopamine regulates the availability of L: -glutamate in the developing striatum. It is also suggested that the application of dopaminergic drugs can interfere with ontogenetic processes within the striatal complex.
    Full-text · Article · Sep 2009
    • Blocking PKA results in a rundown phenomenon. Although a linear rundown in AMPA current was previously reported in striatum spiny medium neurons (Lin et al., 2003), the rundown induced by blocking PKA activity in our work is more rapid and nonlinear . Adding D 1 -receptor agonist failed to reverse or slow the rundown.
    [Show abstract] [Hide abstract] ABSTRACT: Dopamine can modulate and excite spinal locomotor networks, affect afferent transmission and increase motoneuronal excitability. One of the mechanisms whereby dopamine increases motoneuronal excitability is to potentiate AMPA channel-mediated glutamatergic transmission onto motoneurons. However, it is not known which dopaminergic receptor subtypes or the intracellular mechanisms contribute to these effects. In this study, we used whole-cell patch clamp techniques to record chemically evoked AMPA currents in neonatal mouse motoneurons. Bath application of D(1)-like receptor agonist (SKF 39383) increased the AMPA current amplitude and prolonged the decay time constant. In the presence of D(1) receptor antagonist LE300, the effects of DA on AMPA currents were blocked. In contrast, bath-application of the D(2)-like receptor agonist quinpirole did not modulate AMPA currents. In the presence of D(2) receptor antagonist L-741626, dopaminergic modulation of AMPA currents was unaffected. These results suggest that augmentation of AMPA transmission by dopamine is accomplished by D(1) receptor-based mechanisms. This short-term modulation does not appear to involve cycling of AMPA receptor into the membrane, since blocking insertion with botulinum toxin C did not affect the augmentation of AMPA currents after activating D(1) receptors. On the other hand, blocking protein kinase A (PKA) with H-89 completely abolished the effects of D(1) agonists. In addition, we used cell-attached single channel recording to demonstrate that stimulating D(1) receptors increased individual AMPA channel open probability and open duration. Our data demonstrate that dopamine increases the efficacy of glutamatergic transmission onto motoneurons by increasing AMPA conductances via a D(1) PKA-based signaling system.
    Article · Feb 2009
    • membrane fraction of striatal homogenates while Dunah et al. (2004) have shown that deletion of the gene for the protein tyrosine kinase, Fyn, inhibits this D1 receptor-induced enhancement. On the other hand, several studies presented evidence that dopamine can attenuate NMDA-mediated currents (Lee et al. 2002; Lin et al. 2003). In particular Lee et al. (2002) demonstrated inhibition of NMDA responses by a direct protein–protein interaction between the dopamine D1 receptor and NR2A subunit C-termini.
    [Show abstract] [Hide abstract] ABSTRACT: NMDA receptors are of particular importance in the control of synaptic strength and integration of synaptic activity. Dopamine receptor modulation of NMDA receptors in neonatal striatum may influence the efficacy of synaptic transmission in the cortico-striatal pathway and if so, this modulation will affect the behaviour of the basal ganglia network. Here, we show that in acute brain slices of neonatal (P7) rat striatum the dopamine D1 receptor agonist SKF-82958 significantly decreases NMDA receptor currents in patch-clamp whole-cell recordings. This inhibition is not abolished by application of a G protein inhibitor (GDP-beta-S) or irreversible G protein activator (GTP-gamma-S) suggesting a G protein-independent mechanism. In addition, intracellular application of protein tyrosine kinase inhibitors (lavendustin A or PP2) abolished D1 inhibition of NMDA currents. In contrast, in older animals (P28) D1 receptor activation produces a potentiation of the NMDA response which suggests there is a developmental switch in D1 modulation of striatal NMDA receptors. Single-channel recordings show that direct D1 receptor inhibition of NMDA receptors cannot be observed in isolated membrane patches. We hypothesize that D1 inhibition in whole-cell recordings from neonatal rats may be mediated by a change in NMDA receptor trafficking. Consistent with this hypothesis, intracellular application of a dynamin inhibitory peptide (QVPSRPNRAP) abolished D1 inhibition of NMDA receptor currents. We therefore conclude that a tyrosine kinase-dependent alteration of NMDA receptor trafficking underlies D1 dopamine receptor-mediated down-regulation of NMDA receptor currents in medium spiny neurons of neonatal rat striatum.
    Article · Sep 2008
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