Establishment and Maintenance of Neural Circuit Architecture

Abstract

The ability to sense the world, process information, and navigate the environment depends on the assembly and continuous function of neural circuits in the brain. Within the past two decades, new technologies have rapidly advanced our understanding of how neural circuits are wired during development and how they are stably maintained, often for years. Electron microscopy reconstructions of model organism connectomes have provided a map of the stereotyped (and variable) connections in the brain; advanced light microscopy techniques have enabled direct observation of the cellular dynamics that underlie circuit construction and maintenance; transcriptomic and proteomic surveys of both developing and mature neurons have provided insights into the molecular and genetic programs governing circuit establishment and maintenance; and advanced genetic techniques have allowed for high-throughput discovery of wiring regulators. These tools have empowered scientists to rapidly generate and test hypotheses about how circuits establish and maintain connectivity. Thus, the set of principles governing circuit formation and maintenance have been expanded. These principles are discussed in this review.

Figure 1.

Distinction between cellular and subcellular synaptic specificity. A, Neurons can preferentially form synapses with subsets of other neurons. B, Neurons can preferentially form synapses at specific subcellular locations.

Figure 2.

Features of proteins that promote synaptic specificity. A, Molecules that specify connectivity should be at the time of synapse formation. B, High-affinity molecules should be expressed in presynaptic and postsynaptic neurons. C, Nonsynaptic partners should express molecules with relatively low affinity. D, Manipulation of molecule expression (removal or misexpression) should result in circuit miswiring.

Figure 3.

Mechanisms that promote the establishment of synaptic specificity. A, Cell surface cues can promote the proper matching of presynaptic and postsynaptic partners. B, Secreted cues can specify the subcellular location of presynapses. Adapted from Klassen and Shen (2007). C, Secreted cues can specify the subcellular location of postsynaptic sites. Adapted from Sales et al. (2019). D, Patterns of spontaneous neuronal activity influence the organization of OSNs into discrete glomeruli. Adapted from Nakashima et al. (2019).

Figure 4.

Mechanisms that promote neural circuit maintenance. A, Synaptic partnerships and circuit topology are retained through restricting dendritic overgrowth. B, Synapse location is maintained through the positioning of glia-neuron contacts. Adapted from Shao et al. (2013). C, Maintenance of synapse stability is facilitated by the cooperation of ECM-CAM-intracellular scaffold-cytoskeletal interactions. D, Silencing of neuronal activity can result in degeneration or neuron loss.