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Research Articles, Neurobiology of Disease

mTORC2 Inhibition Improves Morphological Effects of PTEN Loss, But Does Not Correct Synaptic Dysfunction or Prevent Seizures

Erin R. Cullen, Kamran Tariq, Amy N. Shore, Bryan W. Luikart and Matthew C. Weston
Journal of Neuroscience 1 February 2023, 43 (5) 827-845; DOI: https://doi.org/10.1523/JNEUROSCI.1354-22.2022
Erin R. Cullen
1Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont 05405
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Kamran Tariq
2Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755
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Amy N. Shore
1Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont 05405
3Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia 24016
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Bryan W. Luikart
2Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755
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Matthew C. Weston
1Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont 05405
3Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia 24016
4School of Neuroscience, Virginia Polytechnic and State University, Blacksburg, Virginia 24061
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Abstract

Hyperactivation of PI3K/PTEN-mTOR signaling during neural development is associated with focal cortical dysplasia (FCD), autism, and epilepsy. mTOR can signal through two major hubs, mTORC1 and mTORC2, both of which are hyperactive following PTEN loss of function (LOF). Here, we tested the hypothesis that genetic inactivation of the mTORC2 complex via deletion of Rictor is sufficient to rescue morphologic and electrophysiological abnormalities in the dentate gyrus caused by PTEN loss, as well as generalized seizures. An established, early postnatal mouse model of PTEN loss in male and female mice showed spontaneous seizures that were not prevented by mTORC2 inactivation. This lack of rescue occurred despite the normalization or amelioration of many morphologic and electrophysiological phenotypes. However, increased excitatory connectivity proximal to dentate gyrus granule neuron somas was not normalized by mTORC2 inactivation. Further studies demonstrated that, although mTORC2 inactivation largely rescued the dendritic arbor overgrowth caused by PTEN LOF, it increased synaptic strength and caused additional impairments of presynaptic function. These results suggest that a constrained increase in excitatory connectivity and co-occurring synaptic dysfunction is sufficient to generate seizures downstream of PTEN LOF, even in the absence of characteristic changes in morphologic properties.

SIGNIFICANCE STATEMENT Homozygous deletion of the Pten gene in neuronal subpopulations in the mouse serves as a valuable model of epilepsy caused by mTOR hyperactivation. To better understand the physiological mechanisms downstream of Pten loss that cause epilepsy, as well as the therapeutic potential of targeted gene therapies, we tested whether genetic inactivation of the mTORC2 complex could improve the cellular, synaptic, and in vivo effects of Pten loss in the dentate gyrus. We found that mTORC2 inhibition improved or rescued all morphologic effects of Pten loss in the dentate gyrus, but synaptic changes and seizures persisted. These data suggest that synaptic dysfunction can drive epilepsy caused by hyperactivation of PI3K/PTEN-mTOR, and that future therapies should focus on this mechanistic link.

  • dentate gyrus
  • epilepsy
  • mTOR
  • mTORC1
  • mTORC2
  • synaptic transmission

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The Journal of Neuroscience: 43 (5)
Journal of Neuroscience
Vol. 43, Issue 5
1 Feb 2023
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mTORC2 Inhibition Improves Morphological Effects of PTEN Loss, But Does Not Correct Synaptic Dysfunction or Prevent Seizures
Erin R. Cullen, Kamran Tariq, Amy N. Shore, Bryan W. Luikart, Matthew C. Weston
Journal of Neuroscience 1 February 2023, 43 (5) 827-845; DOI: 10.1523/JNEUROSCI.1354-22.2022

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mTORC2 Inhibition Improves Morphological Effects of PTEN Loss, But Does Not Correct Synaptic Dysfunction or Prevent Seizures
Erin R. Cullen, Kamran Tariq, Amy N. Shore, Bryan W. Luikart, Matthew C. Weston
Journal of Neuroscience 1 February 2023, 43 (5) 827-845; DOI: 10.1523/JNEUROSCI.1354-22.2022
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Keywords

  • dentate gyrus
  • epilepsy
  • mTOR
  • mTORC1
  • mTORC2
  • synaptic transmission

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