Neuronal sub-compartmentalization: a strategy to optimize neuronal function

Abstract

Neurons are highly polarized cells that consist of three main structural and functional domains: a cell body or soma, an axon, and dendrites. These domains contain smaller compartments with essential roles for proper neuronal function, such as the axonal presynaptic boutons and the dendritic postsynaptic spines. The structure and function of these compartments have now been characterized in great detail. Intriguingly, however, in the last decade additional levels of compartmentalization within the axon and the dendrites have been identified, revealing that these structures are much more complex than previously thought. Herein we examine several types of structural and functional sub-compartmentalization found in neurons of both vertebrates and invertebrates. For example, in mammalian neurons the axonal initial segment functions as a sub-compartment to initiate the action potential, to select molecules passing into the axon, and to maintain neuronal polarization. Moreover, work in Drosophila melanogaster has shown that two distinct axonal guidance receptors are precisely clustered in adjacent segments of the commissural axons both in vivo and in vitro, suggesting a cell-intrinsic mechanism underlying the compartmentalized receptor localization. In Caenorhabditis elegans, a subset of interneurons exhibits calcium dynamics that are localized to specific sections of the axon and control the gait of navigation, demonstrating a regulatory role of compartmentalized neuronal activity in behaviour. These findings have led to a number of new questions, which are important for our understanding of neuronal development and function. How are these sub-compartments established and maintained? What molecular machinery and cellular events are involved? What is their functional significance for the neuron? Here, we reflect on these and other key questions that remain to be addressed in this expanding field of biology.

Keywords: axonal and dendritic sub-compartments; compartmentalization; neuronal activity; neuronal development; patterning; polarization; unipolar neurons.

Figure 1

Neurons contain compartments, which can be further divided into sub‐compartments. (A) Neurons are polarized cells with three main compartments: dendrites, cell body (or soma), and axon. Within each of these compartments, there are domains (sub‐compartments) that can be defined based on their morphology and/or function, such as the synaptic spines present in dendrites, and the presynaptic boutons present in axon terminals. Both are crucial for synaptic activity and plasticity. Organelles can localize in these discrete sub‐compartments to acquire specific functions in spine formation and synaptic transmission; (B) Through immunohistochemistry and electrophysiology it is possible to identify the axonal initial segment; this proximal section of the axon closest to the soma contains an increased number of sodium channels that are necessary for the initiation of the action potential, and a cytoskeletal architecture that functions as a filter for cytoplasmic transport to the distal axon; (C) The neurite of the gonadotropin‐releasing hormone (GnRH) neurons is referred to as a ‘dendron’ because it functions as both a dendrite and an axon. This long projection is divided into three functional sub‐compartments: the proximal dendron, which is necessary for action potential initiation and conduction, the central dendron, which is implicated in action potential conduction, and the distal dendron, which is required for integration of sub‐threshold stimuli. It is still not known how pre‐ and postsynaptic elements are precisely organized in this configuration; (D) The dendrites of starburst amacrine cells, which are involved in detecting the direction of the movement of visual stimuli, show calcium compartmentalization. Schematic representation of the calcium recordings from two opposite regions of the dendritic arborizations (orange and purple cones) during light illumination (blue shaded area), showing an increase in the calcium concentration [Ca⁺⁺] in the illuminated dendrites but not in dendrites on the opposite side. Adapted from Euler et al. (2002).

Figure 2

Compartmentalization of synaptic molecules in the Ring interneurons A (RIAs). (A) Schematic representation of Caenorhabditis elegans in lateral view; the head is on the left, the tail is on the right, the dorsal side is up and the ventral side is down. The RIA interneurons are located in the head of the animal (orange) and the left RIA is schematically represented. The diagram of the wild‐type RIA neuron shows the synaptic compartmentalization of the RIA neurite, with the exclusively postsynaptic proximal region (blue), the asynaptic isthmus region (grey), and the distal region mixed with presynaptic and postsynaptic sites (magenta); (B) In unc-101 mutant animals the postsynaptic region, defined by the localization of the glutamate receptor GLR‐1 (blue), extends to the entire length of the neurite as a result of the lack of receptor retrieval from the distal region, whereas the distal presynaptic region (magenta), defined by the localization of the Ras‐associated binding protein RAB‐3, is unaltered; (C) Conversely, in double mutant cyy-1;cdk-5 animals the presynaptic molecules diffuse towards the dendritic compartment in a dynein‐dependent manner, leaving the distribution of postsynaptic receptors unchanged; (D) Finally, in ttx-7 mutant animals, both the distal presynaptic regions and postsynaptic regions are altered and redistributed throughout the neurite.

Figure 3

Axon guidance receptors compartmentalize in the axon of Drosophila melanogaster neurons. (A) In D. melanogaster, the axons of commissural neurons cross the midline of the ventral nerve cord through the anterior commissure (AC), avoiding the repellent Wingless/Integrated Wnt5 (purple) present on the posterior commissure (PC), and then extend anteriorly. These neurons display striking axonal compartmentalization of the axon guidance receptor molecules Derailed (pink), localized to the proximal region, and Roundabout (ROBO) molecules (orange), localized to the distal region; (B) Intrinsic mechanisms are required for this compartmentalization, as the same pattern of localization is also observed in the neurons in culture in the absence of external guidance cues.

Figure 4

Sub‐compartmentalization of the LIN‐17/Frizzled receptor in Caenorhabditis elegans. In the DA9 motor neurons, a posterior gradient of the LIN‐44/Wnt ligand (green) and a ventral gradient of EGL‐20/Wnt (purple) define the axonal sub‐compartmentalization of LIN‐17/Frizzled receptors, which in turn confines the localization of presynaptic RAB‐3 molecules (gold circles) to the distal segment of the DA9 motor neuron axon (orange). EGL, egg‐laying defective; LIN, abnormal cell lineage; Wnt, wingless.

Figure 5

Calcium compartmentalization in the Caenorhabditis elegans ring interneuron A (RIA) axons. During dorsal head bending, calcium transients are detected in the nerve ring dorsal (nrD) region of the RIA axon (see Fig. 2 for details of the RIA neurons), whereas during ventral head bending the calcium transients are recorded in the nerve ring ventral (nrV) regions. These calcium transients are asynchronous and compartmentalized within the axon. The RIA axonal domains also generate synchronous calcium activity upon sensory stimulation.