Distinct roles of presynaptic dopamine receptors in the differential modulation of the intrinsic synapses of medium-spiny neurons in the nucleus accumbens

Abstract

BackgroundIn both schizophrenia and addiction, pathological changes in dopamine release appear to induce alterations in the circuitry of the nucleus accumbens that affect coordinated thought and motivation. Dopamine acts principally on medium-spiny GABA neurons, which comprise 95% of accumbens neurons and give rise to the majority of inhibitory synapses in the nucleus. To examine dopamine action at single medium-spiny neuron synapses, we imaged Ca2+ levels in their presynaptic varicosities in the acute brain slice using two-photon microscopy.ResultsPresynaptic Ca2+ rises were differentially modulated by dopamine. The D1/D5 selective agonist SKF81297 was exclusively facilitatory. The D2/D3 selective agonist quinpirole was predominantly inhibitory, but in some instances it was facilitatory. Studies using D2 and D3 receptor knockout mice revealed that quinpirole inhibition was either D2 or D3 receptor-mediated, while facilitation was mainly D3 receptor-mediated. Subsets of varicosities responded to both D1 and D2 agonists, showing that there was significant co-expression of these receptor families in single medium-spiny neurons. Neighboring presynaptic varicosities showed strikingly heterogeneous responses to DA agonists, suggesting that DA receptors may be differentially trafficked to individual varicosities on the same medium-spiny neuron axon.ConclusionDopamine receptors are present on the presynaptic varicosities of medium-spiny neurons, where they potently control GABAergic synaptic transmission. While there is significant coexpression of D1 and D2 family dopamine receptors in individual neurons, at the subcellular level, these receptors appear to be heterogeneously distributed, potentially explaining the considerable controversy regarding dopamine action in the striatum, and in particular the degree of dopamine receptor segregation on these neurons. Assuming that post-receptor signaling is restricted to the microdomains of medium-spiny neuron varicosities, the heterogeneous distribution of dopamine receptors on individual varicosities is likely to encode patterns in striatal information processing.

Bidirectional plasticity in striatonigral synapses: A switch to balance direct and indirect basal ganglia pathways

“…Post-tetanic potentiation was not affected, suggesting that there is a margin for the IPSC to grow. The fact that synaptic facilitation was produced by a dopamine agonist that occluded HFS actions suggests that both phenomena have the same cause: presynaptic dopamine D 1 -receptor modulation of striatonigral synapses (Radnikow and Misgeld 1998;Guzmán et al 2003;Mizuno et al 2007;Tecuapetla et al 2007;Aceves et al 2011;Chuhma et al 2011) and suggest that the facilitation phenomenon is not long-term potentiation (LTP).…”

Dopaminergic modulation of short-term synaptic plasticity at striatal inhibitory synapses

“…It reinforces the view that D 2 and D 1 actions represent the static and dynamic branches of the same system. Nonetheless, some unitary connections responded to both D 1 -and D 2 -class agonists, suggesting a degree of colocalization (58)(59)(60). Hence, some sets of terminals may shift their plasticity between the lowest and highest degrees of STD.…”

The application of a rodent-based Morris water maze (MWM) protocol to an investigation of age-related differences in human spatial learning.

“…In order to enhance translational research involving both humans and rodents, the current study applied an experimental protocol adapted from the MWM protocols that were previously employed by Magnusson and colleagues to assess search performance in male mice (see Magnusson, 1998; Magnusson, Scruggs, Zhao, & Hammersmark, 2007; Zhao et al, 2009) to an investigation of age-related differences in spatial learning in human subjects. Critically, in view that the MWM is relevant for assessing age-related declines in spatial learning and memory formation in both humans and mice, we designed a virtual Morris water maze (vMWM) — comprising of simple geometric cues, multiple place trials, and interleaving probe trials — that emulated the procedure of Magnusson et al’s rodent-based protocols (Magnusson, 1998; Magnusson et al, 2007; Zhao et al, 2009) with reference to the number, types and duration of trials, the spatial layout of cues, data-recording procedures, and analytical methods (see Methods, for details).…”

“…Critically, in view that the MWM is relevant for assessing age-related declines in spatial learning and memory formation in both humans and mice, we designed a virtual Morris water maze (vMWM) — comprising of simple geometric cues, multiple place trials, and interleaving probe trials — that emulated the procedure of Magnusson et al’s rodent-based protocols (Magnusson, 1998; Magnusson et al, 2007; Zhao et al, 2009) with reference to the number, types and duration of trials, the spatial layout of cues, data-recording procedures, and analytical methods (see Methods, for details).…”

“…Compatible with the previous data-recording approach taken by Gallagher, Burwell, and Burchinal (1993), and Magnusson and colleagues (Das & Magnusson, 2011; Magnusson, 1997, 1998; Magnusson et al, 2007; Zhao et al, 2009), we applied the proximity measure in our vMWM task to evaluate spatial learning. Prior to this study, proximity had only been used to evaluate the MWM performance of rodents (i.e., rats and mice) (see, e.g., Das & Magnusson, 2011; Gallagher et al, 1993; Magnusson, 1997, 1998; Magnusson et al, 2007; Walsh, Booth, & Poe, 2011; Zhao et al, 2009).…”