Welcome to the Paradis Lab
Research in the Paradis laboratory seeks to define the genes that instruct neurons to establish and modify their connectivity, with the overall goal of understanding how neural network dysfunction contributes to neurological disorders. To this end, we pioneered an unbiased, forward genetic, RNAi-based screen in cultured primary neurons that revealed new genes which function to regulate synapse formation and dendritic morphology. Based on these findings, we identified the activity-regulated, small GTPase Rem2 as an important modulator of synapse formation and neuronal morphology both in vitro in cultured rodent neurons and in the optic tectum of Xenopus tadpoles. Our ongoing studies on Rem2 will reveal important insights into experience-dependent plasticity in an intact nervous system.
Another research focus of the lab is the molecular basis of inhibitory synapse formation, as this is an understudied area of synapse biology that has significant implications for human disease. We discovered that a class 4 Semaphorin, Sema4D, is required for the proper density of inhibitory, GABAergic synapses while having no affect on excitatory synapse formation. We also made the surprising discovery that Sema4D can drive GABAergic synapse formation on a rapid time scale (i.e. less than 30 minutes), and this effect is dependent on the presence of the its high affinity receptor, Plexin B1. Thus, Sema4D/Plexin B1 signaling is one of the few ligand/receptor pairs identified thus far that preferentially regulates inhibitory synapse formation. While we continue to investigate the mechanism of action of Sema4D in mediating GABAergic synapse formation, we are also investigating how we can harness the activity of Sema4D and other synaptogenic factors to drive inhibitory synapse formation in vivo as a potential therapeutic for neurodevelopmental disorders.