Mature hippocampal neurons require LIS1 for synaptic integrity: Implications for cognition Journal Article

Authors: Sudarov, A.; Zhang, X. J.; Braunstein, L.; LoCastro, E.; Singh, S.; Taniguchi, Y.; Raj, A.; Shi, S. H.; Moore, H.; Ross, M. E.
Article Title: Mature hippocampal neurons require LIS1 for synaptic integrity: Implications for cognition
Abstract: Background: Platelet-activating factor acetylhydrolase 1B1 (LIS1), a critical mediator of neuronal migration in developing brain, is expressed throughout life. However, relatively little is known about LIS1 function in the mature brain. We previously demonstrated that LIS1 involvement in the formation and turnover of synaptic protrusions and synapses of young brain after neuronal migration is complete. Here we examine the requirement for LIS1 to maintain hippocampal circuit function in adulthood. Methods: Effects of conditional Lis1 inactivation in excitatory pyramidal neurons, starting in juvenile mouse brain, were probed using high-resolution approaches combining mouse genetics, designer receptor exclusively activated by designer drug technology to specifically manipulate CA1 pyramidal neuron excitatory activity, electrophysiology, hippocampus-selective behavioral testing, and magnetic resonance imaging tractography to examine the connectivity of LIS1-deficient neurons. Results: We found progressive excitatory and inhibitory postsynaptic dysfunction as soon as 10 days after conditional inactivation of Lis1 targeting CA1 pyramidal neurons. Surprisingly, by postnatal day 60 it also caused CA1 histological disorganization, with a selective decline in parvalbumin-expressing interneurons and further reduction in inhibitory neurotransmission. Accompanying these changes were behavioral and cognitive deficits that could be rescued by either designer receptor exclusively activated by designer drug–directed specific increases in CA1 excitatory transmission or pharmacological enhancement of gamma-aminobutyric acid transmission. Lagging behind electrophysiological changes was a progressive, selective decline in neural connectivity, affecting hippocampal efferent pathways documented by magnetic resonance imaging tractography. Conclusions: LIS1 supports synaptic function and plasticity of mature CA1 neurons. Postjuvenile loss of LIS1 disrupts the structure and cellular composition of the hippocampus, its connectivity with other brain regions, and cognition dependent on hippocampal circuits. © 2017 Society of Biological Psychiatry
Keywords: plasticity; cognitive behavior; lis1; dreadd; synaptic homeostasis; synaptic excitation-inhibition
Journal Title: Biological Psychiatry
Volume: 83
Issue: 6
ISSN: 0006-3223
Publisher: Elsevier Science, Inc.  
Date Published: 2018-03-15
Start Page: 518
End Page: 529
Language: English
DOI: 10.1016/j.biopsych.2017.09.011
PROVIDER: scopus
PMCID: PMC5809292
PUBMED: 29150182
Notes: Article -- Export Date: 3 December 2018 -- Source: Scopus
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MSK Authors
  1. Song-Hai Shi
    43 Shi
  2. Xinjun Zhang
    11 Zhang