Lis1 controls dynamics of neuronal filopodia and spines to impact synaptogenesis and social behaviour

Anamaria Sudarov,Debbie Tseng,Margaret Elizabeth Ross,Frank Gooden,Wen‐Biao Gan

doi:10.1002/emmm.201202106

Anamaria Sudarov, Debbie Tseng + Show 3 more

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https://doi.org/10.1002/emmm.201202106

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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.

Highlights

Definition of the mechanisms regulating formation, persistence and elimination of synapses in the developing brain is a major focus in mental health research
In vivo analysis revealed that both dendritic filopodia and spine dynamics are altered in the adolescent brain of Lis1þ/À mice (Figs 1 and 8)
We found a delay in synaptic cluster formation in vitro, reduced spine density in vivo and deficits in social interactions and social novelty recognition in adolescent Lis1þ/À and Lis1cko animals (Figs 4–7)

Summary

Introduction

Definition of the mechanisms regulating formation, persistence and elimination of synapses in the developing brain is a major focus in mental health research. Excitatory synapses are located on dendritic spines, which are actin-rich protrusions located on dendritic shafts. While a majority of dendritic spines are maintained throughout life, many spines are eliminated and new spines are formed that could reflect memories lost or, through new contacts, gained (Grutzendler et al, 2002; Trachtenberg et al, 2002). Dendrites are adorned with long, actin-based motile filopodia that are the predecessor of dendritic spines. Dendritic filopodia rely on their motility in order to sample, test and make synapses to form proper circuits (Ziv & Smith, 1996). Relatively little is known about the regulation of filopodia dynamics and their consequence on spinogenesis, synapse formation and behaviour

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