Dopaminergic neurons inhibit striatal output through non-canonical release of GABA

110

104

Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABA A receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets.dopamine synapse | neuroligin-2 | medium spiny neuron | striatum C hemical synapses comprise presynaptic machinery for transmitter release and postsynaptic machinery for receptor-mediated signal transduction in a neurochemically matched manner. They are classified into Gray type-I and type-II synapses by asymmetric or symmetric membrane density, respectively, of the preand postsynaptic structures (1). Most, if not all, asymmetric and symmetric synapses are excitatory and inhibitory, respectively, as they selectively express ionotropic glutamate or GABA/glycine receptors together with their specific scaffolding proteins (2). Neurochemical matching of chemical synapses is controlled by activity-dependent mechanisms (3, 4), and mediated by transmembrane adhesion proteins and secreted molecules (5). The neuroligin (NL) family comprises postsynaptic adhesion molecules that form transsynaptic contacts with presynaptic neurexins (Nrxn) (6). Of note, NL1 and NL2 are selectively expressed at glutamatergic and GABAergic synapses, respectively (7,8), and are required for activity-dependent specification of the corresponding synapses (9).Midbrain dopamine neurons project densely to the striat...

Section: Discussioncontrasting

confidence: 54%

Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

Uchigashima

Ohtsuka

Kobayashi

et al. 2016

110

104

“…1H). This piece of evidence rules out the possible action of GABA, if DA and GABA were coreleased from dopaminergic neurons as previously documented (29,30), and confirms that the effect of optogenetic manipulation was mediated by DA. It is also noted that the administration of DA antagonists itself elicited a small and steady, although not statistically significant (ANOVA: P = 0.1) increase in the fEPSP amplitude, indicating a possible impact of tonic DA release on basal synaptic transmission in the DG.…”

Section: Significancesupporting

confidence: 85%

Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding

Deng

Aimone

et al. 2016

Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2-expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Overall, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.T he brain structures crucial for memory formation are presumably under the control of the midbrain dopamine (DA) system, which selectively marks experiences that lead to reward (1, 2). In the striatum and the cortex, repetitive pairing of DA input after, but not before, sensorimotor stimulus within a narrow time window promotes structural and functional connectivity (3, 4), which may provide a cellular basis for reward to reinforce specifically an immediate past action. In the hippocampus, a structure that is instrumental in forming memories of contexts and objects making up the experiences (5, 6), DA must be present at the induction of long-term potentiation (LTP) to increase the magnitude of early-and late-phase LTP (7-10). When released during learning, DA also has been found to enhance the reactivation of newly formed neural ensembles (11). The requisite coincidence between the DA signal and the conditioning stimulation may serve to ensure that only inputs concurrent with or occurring shortly before reward are encoded in long-term memory. However, rewarding outcomes often may be delayed, and the involvement of the hippocampus is necessary when an event and its outcome are temporally discontinuous (12). This type of "memory" can be formed rapidly after even a single experience (5,6), and behavioral studies demonstrate that application of DA agonists in the hippocampus hours after training promotes memory maintenance (13,14), indicating that DA released from midbrain projections (Fig. S1) exerts distinct influences on the hippocampus to reinforce memory of earlier events selectively.Here we surveyed the dentate gyrus (DG) of the hippocampus to explore the possible sites and actions of DA. As the first stage of the intrahippocampal trisynaptic loop, the DG receives multiple processed sensory inputs from the entorhinal cortex (EC) and uses conjunctive encoding to integrate them for a memory representation (15). This region, together with area ...

“…There is still uncertainty about how distant and local afferents might control local dopamine release by the ventrally extending dendrites of SNc neurons. Given the mounting evidence for GABA release by dopaminergic neurons (28), further effects beyond control of dopamine release could be predicted, either locally or within regions innervated by SNc neurons. Moreover, axons originating from striosomal neurons have collaterals, at least in rodents, that innervate the pallidum (globus pallidus and/or entopeduncular nucleus), again suggesting the potential for widespread effects of the striosomal system (3).…”

Section: Discussionmentioning

confidence: 99%

Striosome–dendron bouquets highlight a unique striatonigral circuit targeting dopamine-containing neurons

Crittenden

Tillberg

Riad

et al. 2016

133

157

The dopamine systems of the brain powerfully influence movement and motivation. We demonstrate that striatonigral fibers originating in striosomes form highly unusual bouquet-like arborizations that target bundles of ventrally extending dopamine-containing dendrites and clusters of their parent nigral cell bodies. Retrograde tracing showed that these clustered cell bodies in turn project to the striatum as part of the classic nigrostriatal pathway. Thus, these striosome-dendron formations, here termed "striosome-dendron bouquets," likely represent subsystems with the nigro-striato-nigral loop that are affected in human disorders including Parkinson's disease. Within the bouquets, expansion microscopy resolved many individual striosomal fibers tightly intertwined with the dopamine-containing dendrites and also with afferents labeled by glutamatergic, GABAergic, and cholinergic markers and markers for astrocytic cells and fibers and connexin 43 puncta. We suggest that the striosome-dendron bouquets form specialized integrative units within the dopamine-containing nigral system. Given evidence that striosomes receive input from cortical regions related to the control of mood and motivation and that they link functionally to reinforcement and decision-making, the striosome-dendron bouquets could be critical to dopamine-related function in health and disease.dopamine | striosome | striatum | expansion microscopy