Synapse NL · When Neurons Touch-Elucidating the Role of Neuroligins in the Formation, Development, Maturation, and Maintenance of Synapses

The proper coupling between presynaptic and postsynaptic neurons is essential for synaptic signalling. Synapse formation, maturation, and maintenance are controlled by cell adhesion systems that recruit and organise the synaptic protein machinery. One such system comprises presynaptic neurexins and postsynaptic neuroligins. Of the five known neuroligins, neuroligin 1 is specific for excitatory synapses, while neuroligin 2 is specific for inhibitory synapses and Neuroligin 3 is found on both excitatory and inhibitory synapses. The synaptic localisation of neuroligins 4 and 5 is unknown.The neuroligin/neurexin system is critically involved in the accumulation of scaffold and receptor proteins at postsynapses. However, the mechanisms by which this protein recruitment proceeds are still largely unknown. Loss of neuroligins and dysfunction of the neuroligin/neurexin system are associated with synaptic defects in vitro and in vivo, and mutations in neuroligin 3 or 4 cause monogenic forms of autism spectrum disorders (ASD) in humans. Correspondingly, neuroligin 4 deficient mice show social interaction and communication deficits that are reminiscent of ASD.In this study, I will employ a wide spectrum of genetic, biochemical, cell biological, and electrophysiological methods in combination with mice lacking one or multiple neuroligins to (1) identify novel neuroligin interactors, to (2) characterise functional interactions and redundancies among neuroligins and other adhesion proteins with regard to synapse formation, function, and plasticity, and to (3) generate a conditional knock-in mouse for neuroligin 4 and study the autistic phenotype and behavioural responses in the mature brain. These studies will aid in elucidating the function of the neuroligin/neurexin system in the normal brain as well as in synaptopathic conditions, such as ASD, in which the function of the neuroligin/neurexin system is perturbed.