Mature Hippocampal Neurons Require LIS1 for Synaptic Integrity: Implications for Cognition

Biol Psychiatry. 2018 Mar 15;83(6):518-529. doi: 10.1016/j.biopsych.2017.09.011. Epub 2017 Sep 23.


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.

Keywords: Cognitive behavior; DREADD; LIS1; Plasticity; Synaptic excitation-inhibition; Synaptic homeostasis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism*
  • Animals
  • Animals, Newborn
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cell Movement / genetics
  • Clonazepam / pharmacology
  • Cognition / drug effects
  • Cognition / physiology*
  • Conditioning, Psychological / physiology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Fear / physiology
  • GABA Modulators / pharmacology
  • Hippocampus / cytology*
  • Hippocampus / diagnostic imaging
  • Locomotion / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics
  • Neurons / drug effects
  • Neurons / physiology*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Recognition, Psychology / physiology
  • Synapses / drug effects
  • Synapses / physiology*


  • GABA Modulators
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Receptors, G-Protein-Coupled
  • Clonazepam
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Pafah1b1 protein, mouse