Targeting synaptic dysfunction in lissencephaly

ABSTRACT Malformations of cortical development (MCD) are associated with drug-resistant epilepsy, severe intellectual disability and other debilitating co-morbidities. The current proposal is focused on lissencephaly, a severe brain malformation resulting from deletions or mutations in the LIS1 gene. Our work has showed that mice with germline heterozygous mutations in Lis1 exhibit defective neuronal migration during embryonic development and a striking enhancement in glutamate neurotransmission associated with Lis1 deficiency and does not require neuronal disorganization. Building on this work, and our exciting preliminary data suggesting cell adhesion molecules at the synapse might have therapeutic potential in Lis1 mutant mice, we propose a series of pre-clinical translational studies to test whether glutamatergic synapses can be targeted as a disease modifying therapy in lissencephaly. Our approach involves a combination of sophisticated cellular, molecular, electrophysiological and behavior approaches in Lis1+/- mice and human-derived patient neurons. If successful, our results will provide important new information about the effects of genetically-based malformations in driving neurodevelopmental disorder pathologies in vivo and would provide critical proof-of-concept for the therapeutic potential of modifying synaptic function that could be translated into a new targeted therapy for Lis1-associated lissencephaly.