Synaptic Adhesion Molecules and Cognitive Diseases

Wei  Xie

Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education; Institute of Life Sciences, Southeast University, China.

Proper brain function requires correct networks of communicating cells, which are connected by synapses. In these networks, synapses transmit, transform and refine signals. Ample in vitro studies have indicated that synaptic adhesion molecules play important roles in these processes. While homotypic cell adhesion molecules such as Fas II are involved in the initial steps of synaptic recognition and adhesion, heterotypic Neurexin and Neuroligin proteins are thought to be particularly important for establishing the asymmetry of the synapse, including the differential recruitment of pre- and post-synaptic proteins to their respective subcellular compartments. In humans, alterations in genes encoding neurexins or neuroligins have been implicated in autism and other cognitive diseases. It indicates that synaptic cell adhesion molecules are involved in cognition and its disorders.

Drosophila neurexin (dnrx) is expressed in central nervous system and highly enriched in synaptic regions of the ventral ganglion and brain, is required for synapse formation and associative learning in larvae. Similar to its mammalian counterparts, DNRX is essential for synaptic vesicle cycling, which plays critical roles in neurotransmission at neuromuscular junctions (NMJ). Drosophila neuroligin (dnl) is strongly expressed in the embryonic and larval CNS and at the larval neuromuscular junction (NMJ) as well. dnl mutants show an increase in the number of active zones per bouton, but a decrease in the thickness of the subsynaptic reticulum and length of postsynaptic densities, also exhibit a decrease in the total glutamate receptor density and a shift in the subunit composition of glutamate receptors in favor of GluRIIA complexes. In addition to the observed defects in synaptic morphology, dnl mutants show increased transmitter release and altered kinetics of stimulus evoked transmitter release. Importantly, the defects in presynaptic structure, receptor density and synaptic transmission can be rescued by postsynaptic expression of dnl. DNL co-localizes and binds to DNRX in vivo, and interact genetically. Altogether, dnl and dnrx are required for synapse maturation and function. The further works will shed light on the mechanistic bases of neurodevelopmental disease states, such as Autism, using powerful new genetic models.