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Max-Planck-Institut für Experimentelle Medizin

1.         Synaptogenesis, Neuroligins, and Autism


Synaptogenesis, the formation of functional synapses between neurons, is the final step in the development of the central nervous system. In the mammalian brain, it results in the establishment of a neural network, connecting some 1011 nerve cells with up to 1015 synapses. In principle, synaptogenesis takes place in two consecutive steps that are most likely mediated by cell adhesion molecules. First, an arriving axonal growth cone identifies its appropriate partner cell, creating an initial contact, and second, specific axonal and dendritic protein components are recruited to this initial contact site, forming a functional synapse.

The first main focus of our research is on the molecular mechanisms of synaptic cell adhesion and synaptogenesis, with an emphasis on postsynaptic receptor targeting and clustering. Most of our corresponding work concerns the functional role of Neuroligins, a family of cell adhesion proteins whose members are specifically localized to postsynaptic densities, and their interaction partners (Song et al., 1999). Neuroligins are believed to be involved in the formation and consolidation of synaptic contacts, and were implicated in the aetiology of autism in humans. They form a transsynaptic contact with Neurexins (Figure 1), which is thought to trigger synaptogenesis and to serve as a nucleation site for the assembly of pre- and postsynaptic protein scaffolds and subcellular specializations.

Figure 1. The Neurexin-Neuroligin Synaptic Cell Adhesion System. Neuroligins form a trans-synaptic cell adhesion system that plays a central role in the assembly of pre- and postsynaptic protein networks. Via intracellular interactions, Neurexins recruit voltage-dependent Ca2+-channels and components of the secretion machinery to the presynapse. In an analogous manner, Neuroligins recruit neurotransmitter receptors to the postsynapse. CASK, calcium/calmodulin-dependent serine protein kinase; GKAP, guanylate kinase domain-associated protein; mGlu receptor, metabotropic glutamate receptor; Mint, Munc18 interacting protein; NMDA, N-methyl-D-aspartate; ProSAP, proline-rich synapse-associated protein; PSD95, postsynaptic density protein of 95 kDa; SAP90; synaptosome associated protein of 90 kDa; SAPAP, SAP90/PSD95-associated protein; SHANK, SH3 domain and ankyrin repeat containing protein; Veli, vertebrate Lin 7 (Brose, 2007).

A significant experimental effort in the Neuroligin project concentrated on the analysis of triple deletion mutant mice lacking the three most abundant Neuroligin isoforms in mouse brain, Neuroligin-1, -2, and -3. We found that deletion mutant mice lacking Neuroligin expression entirely die shortly after birth due to respiratory failure, but exhibit normal synaptogenesis in the developing brain. The respiratory failure in Neuroligin deficient mice is the consequence of dramatically reduced synaptic transmission and network activity in brainstem centers that control respiration, which in turn is mainly caused by aberrant maturation and function of GABAergic synapses. Our data show that Neuroligins are essential for proper synapse function but not for synaptogenesis per se (Varoqueaux et al., 2006).

An interesting aspect of our Neuroligin work concerns the role of Neuroligins in autism spectrum conditions (ASCs) (Brose, 2007). Autism spectrum conditions (ASCs) are heritable conditions characterized by impaired reciprocal social interactions, deficits in language acquisition, and repetitive and restricted behaviors and interests. In addition to more complex genetic susceptibilities, even mutation of a single gene can lead to ASC. Several such monogenic heritable ASC forms are caused by loss-of-function mutations in genes encoding regulators of synapse function in neurons, including NLGN3 and NLGN4. In collaboration with the groups of H. Ehrenreich in our institute, J. Fischer (Göttingen, Germany), and T. Bourgeron (Paris, France), we found that mice with a loss-of-function mutation in the murine NLGN4 ortholog Nlgn4, which encodes Neuroligin-4, exhibit highly selective deficits in reciprocal social interactions and communication that are reminiscent of ASCs in humans. Our findings indicate that a protein network that regulates the maturation and function of synapses in the brain is at the core of a major ASC susceptibility pathway, and establish Neuroligin-4-deficient mice as genetic models for the exploration of the complex neurobiological disorders in ASCs (Jamain et al., 2008).

Ultrasonic vocalization is disturbed in Neuroligin 4 knock-out mice (Jamain et al., 2008).

A study performed in collaboration with the group of T.C. Südhof (Dallas, USA) showed that in cultured neurons, Neuroligin-1 overexpression increases excitatory but not inhibitory synaptic responses, and potentiates synaptic NMDAR/AMPAR ratios. In contrast, Neuroligin-2 overexpression increases inhibitory, but not excitatory, synaptic responses. Accordingly, deletion of Neuroligin-1 in knock-out mice selectively decreases the NMDAR/AMPAR ratio, whereas deletion of Neuroligin-2 selectively decreases inhibitory synaptic responses. Chronic inhibition of NMDARs or CaM-Kinase II, which signals downstream of NMDARs, suppresses the synapse-boosting activity of Neuroligin-1, whereas chronic inhibition of general synaptic activity suppresses the synapse-boosting activity of Neuroligin-2. Taken together, these data indicate that Neuroligins do not establish, but specify and validate, synapses via an activity-dependent mechanism, with different Neuroligins acting on distinct types of synapses. This hypothesis reconciles the overexpression and knock-out phenotypes and indicates that Neuroligins contribute to the use-dependent formation of neural circuits (Chubykin et al., 2007).

Additional ongoing research projects in the synaptogenesis field are concerned with the role of HECT-type ubiquitin ligases in neurons (Fouladkou et al., 2008), with the functional role of SUMOylation of neuronal/synaptic proteins, and with the role Band 4.1 proteins in nerve cell differentiation and function.

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