Colloquium Retrograde signaling at central synapses Huizhong W. Tao and Mu-ming Poo* Department of Molecular and Cellular Biology, University of California, Berkeley, CA 97420 Transcellular retrograde signaling from the postsynaptic target cell mation processing and storage in the brain, the central synapse to the presynaptic neuron plays critical roles in the formation, must be formed and regulated under appropriate control. Syn- maturation, and plasticity of synaptic connections. We here review apses are formed only between specific pre- and postsynaptic recent progress in our understanding of the retrograde signaling at partners and stabilized at specific locations on the dendrite. developing central synapses. Three forms of potential retrograde Synapse formation is accompanied by a coordinated develop- signals—membrane-permeant factors, membrane-bound factors, ment of pre- and postsynaptic molecular and structural special- and secreted factors—have been implicated at both developing izations, which requires exchanges of information between pre- and mature synapses. Although many of these signals may be and postsynaptic cells at all stages of synapse development, via active constitutively, retrograde factors produced in association anterograde as well as retrograde signaling. with activity-dependent synaptic plasticity, e.g., long-term poten- tiation and long-term depression, are of particular interest, be- (i) Signaling Before Synaptic Contact. After long-range axon path- cause they may induce modification of neuronal excitability and finding, growth cones approach their target cell, and the process synaptic transmission, functions directly related to the processing of synapse formation begins. It is likely that navigation of the and storage of information in the nervous system. growth cone is stalled and axon differentiation begins in re- sponse to factors secreted from the target cell. A potential eural information coded by the action potential is trans- candidate for such a stalling or ‘‘synaptogenic’’ signal is WNT-7a, Nmitted through a chemical synapse in the anterograde which is secreted by granule cells in the cerebellum and found to direction by release of neurotransmitters, neuropeptides, and induce axon and growth cone remodeling in mossy fibers via other protein factors from the presynaptic terminal. These presynaptic Frizzled receptors (4). The latter activates an intra- molecules produce immediate changes in the membrane poten- cellular signaling cascade that represses the activity of glycogen tial as well as long-term structural and metabolic changes in the synthase 3␤ kinase, an enzyme known to regulate the microtu- postsynaptic cell. Over the past several decades, it has become bule cytoskeleton, and produces stable loop-like microtubules in increasingly clear that information exchange at the synapse is the stalled growth cone. The loop-like conformation of micro- bidirectional: the postsynaptic cell also provides a variety of tubules is similar to that adopted during synapse formation (5, retrograde signals to the presynaptic neuron. This reciprocal 6). At the same time, synapsin I, known to be involved in synapse interaction is crucial for the differentiation and maintenance of formation, maturation, and synaptic vesicle transport (7, 8), was the presynaptic cell as well as the formation and maturation of found to be clustered at the remodeled areas of the mossy fiber. the synapse. The general notion of retrograde signaling involves Other potential ‘‘synaptogenic’’ factors include molecules that postsynaptic production of a signal, either constitutively or serve for the guidance of the axon. For example, a target- triggered by synaptic activity, that acts on the presynaptic neuron secreted neurotrophin, brain-derived neurotrophic factor through the following mechanisms. First, the retrograde signal (BDNF), is not only a chemotropic factor for axon growth in can be carried by a membrane-permeant molecule that diffuses culture (9) and in vivo (10) but also a factor that promotes COLLOQUIUM across the plasma membranes from the postsynaptic cell directly presynaptic transmitter secretion (11, 12). into the presynaptic nerve terminal. Second, membrane- impermeant but soluble factors can be packaged and secreted via (ii) Signaling During Initial Cell–Cell Contact and Recognition. Before exocytotic vesicles by the postsynaptic cell and exert the retro- synaptogenesis and formation of postsynaptic spines, motile grade action by binding and activation of receptors on the filopodia extending from the developing dendrites may increase presynaptic membrane. Third, direct signaling through the syn- the probability of encounters between the dendrite and ap- aptic cleft may be accomplished through mediation of physically proaching axon (13). The interaction between specific pre- and coupled pre- and postsynaptic membrane-bound proteins, in- postsynaptic membrane components will lead to selective adhe- cluding transmembrane proteins as well as those secreted and sion and physical stabilization of the contact. In addition, immobilized in the extracellular matrix within the synaptic cleft. downstream signaling may be triggered in both pre- and postsyn- This review will summarize recent progress in the study of aptic cytoplasm, resulting in structural differentiation and retrograde regulation at central synapses, with a focus on the role changes in local subcellular activities. of retrograde interaction in the formation and activity- It is generally assumed that the selective formation of synapses dependent plasticity of synapses. Some aspects of this subject among the large variety of neuronal types (14, 15) depends on have been more extensively reviewed elsewhere (1). An excellent specific recognition molecules on the neuronal surface. Several review of signaling at developing neuromuscular junctions (NMJs) has also appeared recently (2). This paper was presented at the Inaugural Arthur M. Sackler Colloquium of the National Retrograde Signaling During Synaptogenesis Academy of Sciences, ‘‘Neural Signaling,’’ held February 15–17, 2001, at the National Academy of Sciences in Washington, DC. Our present understanding of the process of synaptogenesis is Abbreviations: BDNF, brain-derived neurotrophic factor; LTP, long-term potentiation; LTD, based largely on studies of developing NMJs (2, 3). For central long-term depression; DSI, depolarization-induced suppression of inhibition; NMJ, neuro- nervous system neurons, the mechanisms governing synapse muscular junction. formation and the signaling molecules involved in this process *To whom the correspondence and reprint requests should be addressed. E-mail: are still poorly understood. As the elementary unit for infor- [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.191351698 PNAS ͉ September 25, 2001 ͉ vol. 98 ͉ no. 20 ͉ 11009–11015 Downloaded by guest on September 24, 2021 groups of candidates have now been proposed. One is the quires the extracellular domain of the protein and can be cadherin family of adhesion molecules (16, 17), which are inhibited by addition of soluble ␤-neurexin (neuroligin-1 recep- localized at synapses and have sufficient molecular diversity. tor). Although the presynaptic localization of neurexins remains Cadherins display homophilic binding preferences and exhibit to be demonstrated, neuroligin-1 has been clearly shown to synapse specificity. For example, different cadherins have been localize to the postsynaptic compartment at excitatory synapses found to segregate into different synapses on the same neuron, (31). Neuroligin–neurexin interaction at the cell–cell contact and specific cadherin expression patterns are correlated with may nucleate the assembly of transmitter release machinery neuronal connection patterns in the brain (18). Interfering with through a presynaptic protein scaffold (32–35). cadherin function in vitro leads to the reduction of long-term Protein–protein interactions across the synaptic junction potentiation (LTP) (19), suggesting a role of cadherin in synapse could simultaneously induce retrograde as well as anterograde remodeling that may underlie LTP. In olfactory systems, tar- signaling. In cultured cortical neurons, Dalva et al. (36) found geting of the olfactory neuron axons to the specific glomerulus that ephrinB1 binding to the EphB receptor induces an inter- in the olfactory bulb may be accomplished through the cell- action of EphB with the NMDA subtype of glutamate receptors specific odorant receptors expressed by the olfactory neurons through extracellular domains of these proteins, leading to (20). On the basis of potential molecular diversity (21), the family synaptic recruitment of NMDA receptors. Treatment of eph- of neurexins and their ligands neuroligins may serve as pre- and rinB1 for several days increases the number of NMDA receptor- postsynaptic markers for central neurons. Many variants of containing postsynaptic specializations as well as that of presyn- neurexin exhibit differential expression patterns in the brain, aptic release sites. The kinase activity of EphB is involved in the leading to the suggestion that a given neuronal subpopulation formation of NMDA receptor-containing postsynaptic special- expresses a unique set of neurexins that contribute to the izations, although it is not required for the initial interaction of specificity of neuronal contacts (22). Similarly, Drosophila EphB and NMDA receptors. The localization of ephrinB and Dscam, a family of putative axon guidance