title: Lis1 controls dynamics of neuronal filopodia and spines to impact synaptogenesis and social behaviour.
abstract: LIS1 (PAFAH1B1) mutation can impair neuronal migration, causing lissencephaly in humans. LIS1 loss is associated with dynein protein motor dysfunction, and disrupts the actin cytoskeleton through disregulated RhoGTPases. Recently, LIS1 was implicated as an important protein-network interaction node with high-risk autism spectrum disorder genes expressed in the synapse. How LIS1 might participate in this disorder has not been investigated. We examined the role of LIS1 in synaptogenesis of post-migrational neurons and social behaviour in mice. Two-photon imaging of actin-rich dendritic filopodia and spines in vivo showed significant reductions in elimination and turnover rates of dendritic protrusions of layer V pyramidal neurons in adolescent Lis1(+/-) mice. Lis1(+/-) filopodia on immature hippocampal neurons in vitro exhibited reduced density, length and RhoA dependent impaired dynamics compared to Lis1(+/+) . Moreover, Lis1(+/-) adolescent mice exhibited deficits in social interaction. Lis1 inactivation restricted to the postnatal hippocampus resulted in similar deficits in dendritic protrusion density and social interactions. Thus, LIS1 plays prominently in dendritic filopodia dynamics and spine turnover implicating reduced dendritic spine plasticity as contributing to developmental autistic-like behaviour.
authors.affiliation: Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, USA.
authors.forename: Anamaria
authors.initials: A
authors.lastname: Sudarov
authors.forename: Frank
authors.initials: F
authors.lastname: Gooden
authors.forename: Debbie
authors.initials: D
authors.lastname: Tseng
authors.forename: Wen-Biao
authors.initials: WB
authors.lastname: Gan
authors.forename: Margaret Elizabeth
authors.initials: ME
authors.lastname: Ross
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism* / Q000523:psychology*; D001519:Behavior; D049229:Dendritic Spines / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse