How Nerve Cells Get In Touch - A Molecular Model Of Synapse Formation And Retrograde Signalling In The Brain

Figure: The Neuroligin/b-Neurexin-junction is the core of a newly forming synapse. Postsynaptic Neuroligin interacts with presynaptic b-Neurexin to form a transsynaptic cell-adhesion complex at a developing synapse. Once the junction is formed, Neuroligins and b-Neurexins initiate well characterized intracellular protein-protein-interaction cascades. These lead to the recruitment of proteins of the transmitter release machinery on the presynaptic side and of signal transduction proteins on the postsynaptic side. The resulting transsynaptic link could also function in retrograde and anterograde signalling of mature synapses. CASK and Mint 1 are presynaptic PDZ-domain proteins with a scaffold function; Munc18 and syntaxin are essential components of the presynaptic transmitter release machinery; PSD95, PSD93, SAP102, and S-SCAM are postsynaptic PDZ-domain proteins with a scaffold and assembly function that recruit ion channels (e.g. K+-channels), neurotransmitter receptors (e.g. NMDA receptors) and other signal transduction proteins (GKAP, SynGAP, CRIPT). Full size image available through contact at http://www.mpg.de/news99/news04g_99.jpg

Researchers at the Max Planck Institute for Experimental Medicine, Göttingen/Germany, and at the University of Texas Southwestern Medical Center, Dallas/Texas, characterized a novel family of cell surface proteins that may regulate the generation of functional networks between nerve cells in the brain by inducing synapse formation (Proc. Natl. Acad. Sci. USA 96, 1100-1105; Feb. 2, 1999).

Information in the brain is transmitted at synapses which are highly sophisticated contact zones between a sending and a receiving nerve cell. They have a typical asymmetric structure where the sending, presynaptic part is specialized for the secretion of neurotransmitters and other signalling molecules while the receiving, postsynaptic part is composed of a complex signal transduction machinery.

In the developing human embryo, cell recognition mechanisms with high resolution generate an ordered network of some 1015 synapses, linking about 1012 nerve cells. The extraordinary specificity of synaptic connections in the adult brain is generated in five consecutive steps. Initially, immature nerve cells migrate to their final location in the brain (1). There, they form processes, so called axons. Axons grow, often over quite long distances, into the target region that the corresponding nerve cell is supposed to hook up with (2). Once arrived in the target area, an axon selects its target cell from a large number of possible candidates (3). Next, a synapse is formed at the initial site of contact between axon and target cell. For this purpose, specialized proteins are recruited to the synaptic contact zone (4). Newly formed synapses are then stabilized and modulated, depending on their use (5). These processes result in finely tuned networks of nerve cells that mediate all brain functions, ranging from simple movements to complex cognitive or emotional behaviour.

Until very recently, the molecular mechanisms that regulate synapse formation in the developing brain were completely enigmatic. In particular, it was unknown how an arriving axon selects a partner neuron, how pre- and postsynaptic proteins are recruited to the initial site of synaptic contact, and how synaptic junctions are connected and held together. To shed light on these problems, Ji-Ying Song and Nils Brose, head of a research group at the Max Planck Institute for Experimental Medicine in Göttingen/Germany, studied the biochemical characteristics and cellular localization of Neuroligin 1, a member of a brain-specific family of cell adhesion proteins. In collaboration with Konstantin Ichtchenko and Thomas C. Südhof from the University of Texas Southwestern Medical Center in Dallas/Texas, they discovered that Neuroligin 1 is specifically localized to synaptic junctions, making it the first known synaptic cell adhesion molecule. Using morphological methods with very high resolution, the Göttingen group was able to demonstrate that Neuroligin 1 resides in postsynaptic membranes, its extracellular tail reaching into the cleft that separates postsynaptic nerve cells from the presynaptic axon terminal.

Interestingly, the extracellular part of Neuroligin 1 binds to another group of cell adhesion molecules, the b-Neurexins. Both, Neuroligins and b-Neurexins are the cores of well characterized intracellular protein-protein-interaction cascades. These link Neuroligins to components of the postsynaptic signal transduction machinery and b-Neurexins to the presynaptic transmitter secretion apparatus.

Based on their findings, Brose and colleagues suggest a novel molecular model of synapse formation in the brain. Central to this model is the transsynaptic connection between Neuroligins and b-Neurexins. This Neuroligin/b-Neurexin-junction is formed at the initial site of contact between a presynaptic axon terminal and its target cell. Once this junction is formed, a complex cascade of intracellular protein-protein-interactions leads to the recruitment of the necessary pre- and postsynaptic protein components. A functional synapse is formed. But the model does not only provide a molecular mechanism for synaptogenesis, says Brose. Indeed, the Neuroligin/b-Neurexin-junction allows for direct signalling between the postsynaptic nerve cell and the presynaptic transmitter secretion machinery. Neurophysiologists and cognitive neurobiologists have postulated such retrograde signalling as a functional prerequisite for learning processes in the brain.

"Our model provides an interesting and simple mechanism for retrograde signaling during learning-dependent changes in synaptic connectivity", Brose says "but we now have to test our predictions". The Göttingen group is currently examining their working hypothesis using mutant mice that completely lack Neuroligins.

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