Synapse Elimination Review and Indelible Memory Where One, or at Most a Few, Identifiable Motor Neurons Innervate Each Identifiable Muscle Fiber, Forming a Ste- Reotyped Circuit Exclusively Dedicated to a Particular Contact with Their Targets. in a Similar Vein, Mechanisms

where one, or at most a few, identifiable motor neurons innervate each identifiable muscle fiber, forming a stereotyped circuit exclusively dedicated to a particular Jeff W. Lichtman*‡ and Howard Colman† *Department of Anatomy and Neurobiology †Department of Neurology function (Figure 1). The greater degree of redundancy Washington University School of Medicine is perhaps the most salient difference between the large St. Louis, Missouri 63110 nervous systems of typical vertebrates and the much smaller nervous systems of invertebrates. If the principle difference in brain size between inverDetermining the way in which memories are stored in tebrates and terrestrial vertebrates were due to neuronal the brain is one of neurobiology’s great remaining chalredundancy, then one consequence would be a fundalenges. One approach to this question has been to ask mental change in the organization of synaptic circuitry. what kinds of changes are taking place during postnatal Taking neuromuscular connectivity as an example, one development when the brain is changing in response to might expect that if muscles were comprised of many environmental cues. This was the approach that led hundreds or thousands of identical fibers, then each Hubel and Wiesel to discover a developmentally remotor neuron projecting to a muscle should be able to stricted competition between the eyes for control of innervate many of the identical fibers, causing extensive cortical space (Wiesel, 1982) and, subsequently, led othaxonal divergence (Figure 2, top). At the same time, ers to discover evidence that seemingly analogous commultiple duplicated motor axons should be appropriate petitive events occur in other parts of the developing partners for each muscle fiber, causing axonal convernervous system (reviewed by Purves and Lichtman, gence (Figure 2, middle). In a nervous system with re1980). dundant neurons and redundant postsynaptic targets, One hallmark of these developmental refinements in the result of simultaneous divergence and convergence synaptic circuitry is the elimination of axonal connecwould be a set of highly overlapping circuits, in which tions. In the visual system, thalamocortical axons diseach target cell could receive convergent innervation connect from cortical layer IV cells (Hubel et al., 1977); in from many neurons and each input could diverge to the cerebellum, climbing fibers disconnect from Purkinje many target cells (Figure 2, bottom). Interestingly, such cells (Crepel et al., 1976; Lohof et al., 1996); in autonomic a pattern is the basic circuit plan of the neuromuscular ganglia, preganglionic inputs disconnect from ganglion system in developing terrestrial vertebrates. It is also cells (Lichtman, 1977); and at the neuromuscular juncthe case that throughout the central nervous system tion, motor axons disconnect from muscle fibers. In each vast overlapping webs of converging and diverging inof these areas, elaboration of synapses by the remaining puts between populations of similar neurons make it axon or axons also occurs. Thus, while some inputs are difficult to describe the circuit diagram. being eliminated, others are becoming stronger. The In vertebrate neuromuscular systems, this kind of exrationale for this selective synapse loss as a means of cessive fan-out and fan-in is only transitory because refining circuitry is the subject of this review. synapse loss reduces the number of inputs innervating What follows is a peripheral view of synaptic refineeach muscle fiber (Figure 3, upper panels). In invertements based mostly on what is known about synapse brates, such a reductive mechanism seems unneceselimination at the mammalian neuromuscular junction. sary because, as far as is known, no early stage of Owing to the greater accessibility and simplicity of deextensive overlap exists. Thus, in a peculiar way, the veloping neuromuscular connections when compared ontogeny of the vertebrate neuromuscular system leads to connections in the brain (Sanes and Lichtman, 1999), to a pattern that is ultimately more invertebrate-like. it has been possible to describe the process in greater After the phase of synapse elimination, each axon has detail than elsewhere. One of the challenges for the its own unique circuit. Thus, synapse elimination can future will be to see whether the conclusions reached be viewed as a mechanism that creates large numbers from studies of the peripheral nervous system apply to of specific circuits out of initially more diffuse and reduncentral synapses. dant connections (Figure 3, lower panels). It is important to emphasize that the kind of elimination Phylogenetic Origins of Synapse Elimination described above (in which the number of axons that At the vertebrate neuromuscular junction, synapse elimiinnervate a target cell is permanently reduced) is only nation refines connections between populations of preone form of synapse elimination. For example, in an and postsynaptic partners. In vertebrates (except fish), invertebrate (Aplysia), long-term habituation of a behaveach motor neuron is always part of a pool of tens ior or pharmacologically induced depression is associor hundreds of similar neurons that serve a common ated with decreases in the number, size and vesicle purpose. Likewise, in vertebrates each identifiable muscomplement of sensory neuron active zones (Bailey and cle is composed of hundreds or thousands of similar Chen, 1988, 1989; Bailey et al., 1992). These structural muscle fibers. This reduplicated arrangement contrasts changes reduce synapse number but may not have any with the pattern of connections in invertebrate muscle, effect on input number. Indeed, the rapid reversibility of behaviors like habituation (i.e., dishabituation) would seem to require that axons retain some kind of synaptic ‡ To whom correspondence should be addressed (e-mail: jeff@