•Striatal dopamine release is mediated by vesicular exocytosis.•Active zone-like sites are required for rapid and efficient dopamine secretion.•Localized dopamine release generates signaling hotspots ...and is powerfully regulated.•Some striatal dopamine release is independent of ascending action potentials.•Future work should assess triggering and sensing mechanisms for fast dopamine coding.
Dopamine controls motor functions, motivation, and reward-related learning through G-protein coupled receptor signaling. The current working model is that upon release, dopamine diffuses to influence many target cells via wide-spread receptors. Recent studies, however, suggest that dopamine release is fast and generates small signaling hotspots. In this review, we summarize progress on the understanding of the dopamine release apparatus and evaluate how its properties may shape dopamine signaling during firing. We discuss how mechanisms of regulation may act through this machinery and propose that striatal architecture for dopamine signaling may have evolved to support rapid dopamine coding.
Most neuronal communication relies upon the synchronous release of neurotransmitters, which occurs through synaptic vesicle exocytosis triggered by action potential invasion of a presynaptic bouton. ...However, neurotransmitters are also released asynchronously with a longer, variable delay following an action potential or spontaneously in the absence of action potentials. A compelling body of research has identified roles and mechanisms for synchronous release, but asynchronous release and spontaneous release are less well understood. In this review, we analyze how the mechanisms of the three release modes overlap and what molecular pathways underlie asynchronous and spontaneous release. We conclude that the modes of release have key fusion processes in common but may differ in the source of and necessity for Ca(2+) to trigger release and in the identity of the Ca(2+) sensor for release.
• We are only beginning to understand the mechanisms of active zone assembly.• Trafficking, protein complex assembly, and membrane anchoring mechanisms are needed.• Ablation of individual active zone ...proteins has mild effects on assembly.• Assembly mechanisms are highly redundant and no master organizer controls it.• Liquid–liquid phase separation principles may control active zone assembly.
In a presynaptic nerve terminal, the active zone is composed of sophisticated protein machinery that enables secretion on a submillisecond time scale and precisely targets it toward postsynaptic receptors. The past two decades have provided deep insight into the roles of active zone proteins in exocytosis, but we are only beginning to understand how a neuron assembles active zone protein complexes into effective molecular machines. In this review, we outline the fundamental processes that are necessary for active zone assembly and discuss recent advances in understanding assembly mechanisms that arise from genetic, morphological and biochemical studies. We further outline the challenges ahead for understanding this important problem.
At each of the brain’s vast number of synapses, the presynaptic nerve terminal, synaptic cleft, and postsynaptic specialization form a transcellular unit to enable efficient transmission of ...information between neurons. While we know much about the molecular machinery within each compartment, we are only beginning to understand how these compartments are structurally registered and functionally integrated with one another. This review will describe the organization of each compartment and then discuss their alignment across pre- and postsynaptic cells at a nanometer scale. We propose that this architecture may allow for precise synaptic information exchange and may be modulated to contribute to the remarkable plasticity of brain function.
Brain function relies on precise synaptic transmission. Biederer, Kaeser, and Blanpied describe the architecture of the nerve terminal, synaptic cleft, and postsynaptic density and the alignment of these compartments. This striking transcellular nanoscale organization may control synapse function.
Dopamine is a prototypical neuromodulator that controls circuit function through G protein-coupled receptor signalling. Neuromodulators are volume transmitters, with release followed by diffusion for ...widespread receptor activation on many target cells. Yet, we are only beginning to understand the specific organization of dopamine transmission in space and time. Although some roles of dopamine are mediated by slow and diffuse signalling, recent studies suggest that certain dopamine functions necessitate spatiotemporal precision. Here, we review the literature describing dopamine signalling in the striatum, including its release mechanisms and receptor organization. We then propose the domain-overlap model, in which release and receptors are arranged relative to one another in micrometre-scale structures. This architecture is different from both point-to-point synaptic transmission and the widespread organization that is often proposed for neuromodulation. It enables the activation of receptor subsets that are within micrometre-scale domains of release sites during baseline activity and broader receptor activation with domain overlap when firing is synchronized across dopamine neuron populations. This signalling structure, together with the properties of dopamine release, may explain how switches in firing modes support broad and dynamic roles for dopamine and may lead to distinct pathway modulation.
Neurovascular interactions are essential for proper brain function. While the effect of neural activity on cerebral blood flow has been extensively studied, whether or not neural activity influences ...vascular patterning remains elusive. Here, we demonstrate that neural activity promotes the formation of vascular networks in the early postnatal mouse barrel cortex. Using a combination of genetics, imaging, and computational tools to allow simultaneous analysis of neuronal and vascular components, we found that vascular density and branching were decreased in the barrel cortex when sensory input was reduced by either a complete deafferentation, a genetic impairment of neurotransmitter release at thalamocortical synapses, or a selective reduction of sensory-related neural activity by whisker plucking. In contrast, enhancement of neural activity by whisker stimulation led to an increase in vascular density and branching. The finding that neural activity is necessary and sufficient to trigger alterations of vascular networks reveals an important feature of neurovascular interactions.
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•Neural activity promotes the formation of vascular networks in the cerebral cortex•Sensory deprivation reduces vascular complexity in layer IV of the barrel cortex•Genetic impairment of neurotransmitter release impairs cortical vascular structure•Activity induced vascular changes occur in absence of neuroarchitectural changes
Using genetic, imaging, and computational tools, Lacoste et al. demonstrate that “natural” neural activity triggered by sensory stimuli enhances the complexity of vascular networks in the mouse cerebral cortex during postnatal development.
Dopamine controls essential brain functions through volume transmission. Different from fast synaptic transmission, where neurotransmitter release and receptor activation are tightly coupled by an ...active zone, dopamine transmission is widespread and may not necessitate these organized release sites. Here, we determine whether striatal dopamine secretion employs specialized machinery for release. Using super resolution microscopy, we identified co-clustering of the active zone scaffolding proteins bassoon, RIM and ELKS in ∼30% of dopamine varicosities. Conditional RIM knockout disrupted this scaffold and, unexpectedly, abolished dopamine release, while ELKS knockout had no effect. Optogenetic experiments revealed that dopamine release was fast and had a high release probability, indicating the presence of protein scaffolds for coupling Ca2+ influx to vesicle fusion. Hence, dopamine secretion is mediated by sparse, mechanistically specialized active zone-like release sites. This architecture supports spatially and temporally precise coding for dopamine and provides molecular machinery for regulation.
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•Striatal dopamine axons contain active zone-like sites with bassoon, RIM, and ELKS•RIM is essential for scaffolding and dopamine exocytosis, but ELKS is dispensable•These mechanistically specialized sites support a high initial release probability•Only ∼30% of dopamine varicosities contain active zone-like sites
Secretion of dopamine requires specialized release machinery.
Highlights • Methods to measure RRP are reviewed and their assumptions and limitations discussed. • Action potential trains can be used to measure the physiologically relevant RRP. • Activation of a ...release site by Munc13 and RIM is necessary for RRP generation. • RRP comprises docked vesicles and rapidly recruited undocked vesicles. • Linking ultrastructure, molecular mechanisms and RRP measurements remains a challenge.
Information flow in neurons proceeds by integrating inputs in dendrites, generating action potentials near the soma, and releasing neurotransmitters from nerve terminals in the axon. We found that in ...the striatum, acetylcholine-releasing neurons induce action potential firing in distal dopamine axons. Spontaneous activity of cholinergic neurons produced dopamine release that extended beyond acetylcholine-signaling domains, and traveling action potentials were readily recorded from dopamine axons in response to cholinergic activation. In freely moving mice, dopamine and acetylcholine covaried with movement direction. Local inhibition of nicotinic acetylcholine receptors impaired dopamine dynamics and affected movement. Our findings uncover an endogenous mechanism for action potential initiation independent of somatodendritic integration and establish that this mechanism segregates the control of dopamine signaling between axons and somata.
To achieve the functional polarization that underlies brain computation, neurons sort protein material into distinct compartments. Ion channel composition, for example, differs between axons and ...dendrites, but the molecular determinants for their polarized trafficking remain obscure. Here, we identify mechanisms that target voltage-gated Ca2+ channels (CaVs) to distinct subcellular compartments. In hippocampal neurons, CaV2s trigger neurotransmitter release at the presynaptic active zone, and CaV1s localize somatodendritically. After knockout of all three CaV2s, expression of CaV2.1, but not CaV1.3, restores neurotransmitter release. We find that chimeric CaV1.3s with CaV2.1 intracellular C-termini localize to the active zone, mediate synaptic vesicle exocytosis, and render release sensitive to CaV1 blockers. This dominant targeting function of the CaV2.1 C-terminus requires the first EF hand in its proximal segment, and replacement of the CaV2.1 C-terminus with that of CaV1.3 abolishes CaV2.1 active zone localization and function. We conclude that CaV intracellular C-termini mediate compartment-specific targeting.
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•CaV2.1s, but not CaV1.3s, are at the active zone and trigger neurotransmitter release•Swapping the CaV2.1 C-terminus onto CaV1.3 confers active zone targeting to CaV1.3•CaV1.3 with the CaV2.1 C-terminus mediates release that is L-type blocker sensitive•The first EF hand in the C-terminus is required for CaV2.1 active zone targeting
Voltage-gated Ca2+ channel subtypes are differentially sorted into the soma, dendrites, and axon of a neuron. Chin et al. find that the intracellular C-termini of CaV1 and CaV2 channels are key determinants for compartment targeting and report an essential trafficking role for the first EF hand of CaV2.1.
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