Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors

Abstract

Striatal D2-type dopamine receptors (D2Rs) are implicated in the pathophysiology of neuropsychiatric disorders, including Parkinson’s disease and schizophrenia. Although these receptors regulate striatal synaptic plasticity, the mechanisms underlying dopaminergic modulation of glutamatergic synapses are unclear. We combined optogenetics, 2-photon microscopy, and glutamate uncaging to examine D2R-dependent modulation of glutamatergic synaptic transmission in mouse striatopallidal neurons. We find that D2R activation reduces corticostriatal glutamate release and attenuates both synaptic- and action potential-evoked Ca influx into dendritic spines by approximately 50%. Modulation of Ca signaling is mediated by a PKA-dependent regulation of Ca entry through NMDA-type glutamate receptors that is inhibited by D2Rs and enhanced by activation of 2A-type adenosine receptors (A2ARs). D2Rs also produce a PKA- and A2AR-independent reduction in Ca influx through R-type voltage-gated Ca channels. These findings reveal that dopamine regulates spine Ca by multiple pathways and that competitive modulation of PKA controls NMDAR-mediated Ca signaling in the striatum.

Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission

“…The effect of H89 after quinpirole (8.6 ± 1.4% depression) was significantly smaller than that of H89 applied alone [38.8 ± 5.1% depression; t test t (8 LTD (38). This finding for layer 5 PFC pyramidal cells is in contrast to a previous report suggesting a lack of cAMP/PKA signaling in D2R inhibition of NMDA currents in CA1 pyramidal neurons (31), but is in keeping with the mechanisms proposed to underlie the D2R-dependent decrease in NMDAR-dependent calcium influx in striatopallidal neurons (39).…”

“…That TFS resulted in LTD selectively of EPSC NMDA , but not of EPSC AMPA , indicates that LTD of NMDA transmission is not likely to rely on a decrease in transmitter release (39). Several mechanisms have been postulated for LTD of NMDARs, including internalization of receptors (37), diffusion of receptors to extrasynaptic sites (40), or a switch in NMDAR subunits (41).…”

Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors

“…The mechanisms underlying the distinct role of each pathway thus need to be carefully interpreted. The present study has demonstrated that not only the pathway-specific postsynaptic D1 and D2 receptors but also several key receptors characteristic of the corticostriatal synapses play a pivotal role in the associative reward-based and aversive learning (10)(11)(12). We thus propose a mechanistic model for reward and aversive learning by focusing on the transmission modulation of the corticostriatal synapses in the NAc (Fig.…”

“…The activation of postsynaptic A2a receptors efficiently impedes the synthesis of endocannabinoids and results in suppression of the presynaptic CB1 receptors in glutamatergic neurons through reduced retrograde transmission of endocannabinoids (13,25). Electrophysiological studies have indicated that when the D2 receptors in the indirect-pathway neurons are inhibited or the striatal DA levels are reduced, the NMDA receptors and A2a receptors are coactivated and that elaborate synaptic modulation via the NMDA, A2a, and CB1 receptors induces LTP in glutamatergic transmission in the indirect-pathway neurons (10)(11)(12). Therefore, we examined whether these key neurotransmitter receptors could be involved in aversive learning by infusing the inhibitors or activator of these respective receptors into the intact side of the NAc of the I-aRNB mice.…”

Calcium Signaling in Dendritic Spines

“…Approximately 15% of the current through NMDARs is mediated by Ca 2þ influx under physiological conditions (Schneggenburger et al 1993;Jane et al 2009). Thus, NMDARs are the predominant source of synaptic Ca 2þ signals in a variety of cells, including pyramidal neurons in both the CA1 (Müller and Connor 1991;Regehr and Tank 1992;Mainen et al 1999;Yuste et al 1999;Kovalchuk et al 2000;Sobczyk et al 2005;Bloodgood and Sabatini 2007b) and CA3 (Reid et al 2001) regions of the hippocampus, spiny stellate (Nevian and Sakmann 2004), and pyramidal neurons of the neocortex (Koester and Sakmann 1998;Schiller et al 1998), striatal medium spiny neurons (Carter and Sabatini 2004;Higley and Sabatini 2010), and olfactory granule cells (Egger et al 2005). Because NMDARs are usually located on dendritic spines, their activation by glutamate produces a highly compartmentalized Ca 2þ transient that is largely limited to the activated spine, and blocking NMDAR activation with pharmacological antagonists such as APV or CPP typically reduces or eliminates synaptic Ca 2þ signals in spines Sobczyk et al 2005).…”