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Molecules, maps and synapse specificity

Key Points

  • Synaptogenesis is the culmination of a continuous process, which can be divided into the following stages: (1) axon guidance or pathfinding; (2) gross target recognition; (3) fine target recognition; and (4) elaboration of synaptic contacts onto appropriate cellular domains. Furthermore, synaptic connections are organized topographically, an essential anatomical substrate for orderly 'maps' of sensory surfaces, such as the retina.

  • Sperry proposed that the topographically ordered distribution of synapses was established by “highly specific cytochemical affinities” between an axon and the environment through which it grows, and ultimately its target neuron. He proposed an orderly mapping of two or more standing gradients that are orthogonal to one another, so that an incoming axon is guided by signals encoding both latitude and longitude. Subsequent models have addressed the nature of standing gradients, and how a growth cone might sense and respond to the subtle differences in the molecular environment generated by such gradients.

  • Haydon and Drapeau proposed two general modes of synapse specification. 'Selective' neurons send their neurites only to their appropriate target; 'promiscuous' neurons form synapses with a number of targets, and final specificity is achieved by pruning away the incorrect terminal sites in an activity-mediated process.

  • Neuronal differentiation is the first step in synapse specification. Neurons, and the position they hold within a larger group, impart information. Group identification might be encoded, at least in part, by differential adhesion, and neighbour relationships within groups might be established by gap-junction-mediated communication, or by regulated patterns of calcium waves.

  • The final topographic order of axons within a target might reflect an ordered distribution of axons within a fibre tract. However, retinal axon ordering alone does not seem to be sufficient for dorsoventral patterning in the optic tectum.

  • In the dorsal thalamus, collections of neurons born contemporaneously parse into distinct nuclei. It is remarkable that targeting is precise from the earliest stages of innervation, because thalamic axons from different nuclei travel together through a similar environment, and are presented with an array of possible areal targets.

  • Presynaptic assembly cannot be entirely nonspecific, or all potential partners brought into close proximity would form synapses with each other. Evidence indicates that a particular recognition threshold must be passed in order for synapse-initiation molecules to link. In vitro studies indicate that an interaction between β-neurexin and neuroligins can trigger synapse initiation. Several other molecules have been suggested to be involved in the early stages of synapse recognition/initiation, including EphB and Narp.

  • Stabilizing a synapse is likely to require various molecules, but activity seems to be essential; strong evidence indicates that neurotrophins are involved, and recent work indicates that local synthesis of synaptic proteins might also be important. In Drosophila, homophilic binding between pre- and postsynaptically localized Fasciclin II is required to maintain a neuromuscular synapse, and members of the cadherin superfamily might have a similar role in vertebrates.

  • Synaptogenesis should be viewed as an ongoing process that includes the modification and elimination of existing synapses and the generation of new synapses. Consistent with this, several guidance and recognition molecules continue to be expressed in adult nervous systems, and many have been implicated in the generation of synapse plasticity.

Abstract

A striking feature of the mature central nervous system is the precision of the synaptic circuitry. In contemplating the mature circuitry, it is impossible to imagine how more than 20 billion neurons in the human brain become precisely connected through trillions of synapses. Remarkably, much of the final wiring can be established in the absence of neural activity or experience; so the algorithms that allow precise connectivity must be encoded largely by the genetic programme. This programme, honed over nearly one billion years of evolution, generates networks with the flexibility to respond to a wide range of physiological challenges. There are several contemporary models of how synapse specificity is achieved, many of them proposed before the identification of guidance or recognition molecules. Here we review a selection of models as frameworks for defining the nature and complexity of synaptogenesis, and evaluate their validity in view of progress made in identifying the molecular underpinnings of axon guidance, targeting and synapse formation.

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Figure 1: The process of targeting a synapse.
Figure 2: Models for achieving synapse specificity.
Figure 3: Contact-mediated recognition proteins and their binding partners.
Figure 4: Synapse between 6-day-old cultured hippocampal neurons.
Figure 5: A simple model of afferent-dependent cadherin clustering.

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Acknowledgements

Our work is generously supported by the Corrinne Goldsmith Dickinson Center for Multiple Sclerosis; the Bachmann-Strauss Dystonia and Parkinson Foundation, Inc.; the Christopher Reeve Paralysis Foundation; Irma T Hirschl Career Scientist Awards; a New York State Department of Health Spinal Cord Injury Trust Award; and by National Institutes of Health US Public Health Service awards to D.L.B., D.R.C. and G.W.H. We thank A. Bergemann for his comments on the manuscript.

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Correspondence to Deanna L. Benson.

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DATABASES

FlyBase

Fasciclin II

Fasciclin III

Lar

N-cadherin

Netrin

Semaphorin II

GenBank

axonin-1

BMP4

F11

N-cadherin

β-neurexin

NgCAM

NrCAM

Tbx5

Vax

ventroptin

LocusLink

BMP7

cadherin

EphA

EphB

ephrin

FGF8

integrin

L1

LAMP

Narp

N-cadherin

α-N-catenin

neurofascin

neuroligin 1

neuroligin 2

neuropilin 1

neuropilin 2

NrCAM

protocadherin

semaphorin III

Glossary

INTERNAL CAPSULE

A large bundle of axons that reciprocally connects the cortex with the subcortical structures of the brain.

SPLIT BRAIN

A brain in which the two hemispheres have been separated by severing the commissures that connect them. Sperry carried out his original experiments on a patient whose corpus callosum had been cut to treat epilepsy. This work showed that both halves of the brain can function independently, and that the brain is functionally asymmetrical.

MULTIPLE CONSTRAINTS MODEL

Any model in which multiple rules or variables operate in concert.

HELISOMA

A freshwater pond snail with a brown shell in the shape of a flattened spiral.

HOMOPHILIC BINDING

Adhesion that is mediated through attraction between identical molecules expressed by different cells.

RHOMBOMERES

Neuroepithelial segments found transiently in the embryonic hindbrain that adopt distinct molecular and cellular properties, restrictions in cell mixing, and ordered domains of gene expression.

BARRELS

Cylindrical columns of neurons seen in the rodent neocortex. Each barrel receives sensory input from a single whisker follicle, and the topographical organization of the barrels corresponds precisely to the arrangement of whisker follicles on the face.

GPI

Glycosyl phosphatidylinositol. A post-translational modification, the function of which is to attach proteins to the exoplasmic leaflet of membranes, possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol, and is attached to the protein through an ethanolamine phosphate moiety.

RECEPTOR TYROSINE PHOSPHATASES

Also known as receptor-like protein tyrosine phosphatases (RPTPs), these are transmembrane signal transduction proteins that modulate the levels of tyrosine phosphorylation in the cell. Their intracellular domains catalyse the dephosphorylation of specific tyrosine residues on their target proteins. Signalling through RPTPs is thought to be important for various developmental processes, including axon growth and guidance.

PROPRIOCEPTIVE

Relating to the perception of position and movement of the body parts, in response to stimuli generated within the body.

CHANDELIER CELL

A type of cortical GABA-expressing inhibitory interneuron. One of its distinguishing features is that its axon terminates on the axon initial segment of its target cell.

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Benson, D., Colman, D. & Huntley, G. Molecules, maps and synapse specificity. Nat Rev Neurosci 2, 899–909 (2001). https://doi.org/10.1038/35104078

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