Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons

Abstract

Mesoaccumbens fibers are thought to co-release dopamine and glutamate. However, the mechanism of co-release of dopamine and glutamate is unclear, and the co-release by mesoaccumbens fibers has not been documented. By electron microcopy we showed that some mesoaccumbens fibers have vesicular transporters for dopamine (VMAT2) in axon-segments continuous with axon-terminals that lack VMAT2, but contain vesicular glutamate transporters type 2 (VGluT2). In vivo overexpression of VMAT2 did not change segregation of the two vesicular types, suggesting highly regulated mechanisms for maintaining this segregation. The mesoaccumbens axon terminals containing VGluT2-vesicles make asymmetric synapses; commonly associated with excitatory signaling. By optogenetics, we showed release of dopamine and glutamate from mesoaccumbens fibers. These findings reveal a complex type of signaling by mesoaccumbens fibers in which dopamine and glutamate although can be released from the same axons; they are not normally released at the same site or from the same synaptic vesicles.

Cross-hemispheric dopamine projections have functional significance

“…Similar D2 regulation in both hemispheres accompanied hemispherically equivalent release in the contralateral DMS, in contrast to D2 regulation of contralateral/ipsilateral VTA projections. Based on the confirmation of our findings using optogenetics, contralateral dopamine release is driven by dopamine neurons; however, optical activation does not preclude the effects of glutamate corelease (41), which may facilitate hemispherically equivalent release.…”

Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens

“…DA and glutamate are co-released from VTA DA neurons (21)(22)(23) and share several release properties (20). We observed that the M 5 mAChR-mediated potentiation affects oEPSCs recorded from spiny projection neurons in a similar fashion as oDA transients evoked by direct optogenetic stimulation of DA axonal projections (Fig.…”

“…However, the degree of potentiation of oEPSCs by muscarinic agonists was significantly reduced in vGluT 2 -cre compared with DAT-cre mice, suggesting M 5 mAChRs activity preferentially regulates DA releasing neurons. Recently, Zhang et al (23) reported that dopaminergic and glutamatergic vesicular systems coexist, but segregate to different compartments of the same axonal projections. This observation raises the possibility that the number and/or coupling efficiency of M 5 mAChRs can be differentially expressed at these two compartments within the same axonal projection, favoring glutamate over DA transmission ( Fig.…”

“…A subset of DA neurons in the VTA co-releases DA and glutamate in the NAc shell (21)(22)(23). We recently showed that the release properties and the modulation by G i -coupled D 2 receptors are remarkably similar for DA and glutamate release from these terminals (20).…”

“…A small subset of tyrosine-hydroxylase-positive (TH) neurons also express vGluT 2 mRNA (TH/vGluT 2 neurons) and co-release glutamate. This area also contains neurons lacking TH that express vGluT 2 mRNA (vGluT 2 -only neurons) and send projections to the NAc (23,26). We tested whether the mAChR-dependent potentiation of DA transmission occurs in all midbrain axonal projections to the NAc or is, rather, restricted to a subset of them.…”