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Research Article

Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism

Pablo Garcia-Junco-Clemente, David K. Chow, Elaine Tring, Maria T. Lazaro, Joshua T. Trachtenberg, and Peyman Golshani
  1. Departments of aNeurobiology and
  2. bNeurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095

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PNAS first published October 21, 2013; https://doi.org/10.1073/pnas.1309207110
Pablo Garcia-Junco-Clemente
Departments of aNeurobiology and
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David K. Chow
Departments of aNeurobiology and
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Elaine Tring
Departments of aNeurobiology and
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Maria T. Lazaro
bNeurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095
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Joshua T. Trachtenberg
Departments of aNeurobiology and
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Peyman Golshani
bNeurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095
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  • For correspondence: pgolshani@mednet.ucla.edu
  1. Edited by Bernardo Sabatini, Harvard Medical School, Boston, MA, and accepted by the Editorial Board September 25, 2013 (received for review May 15, 2013)

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Significance

Advances in human genetics have identified many gene alterations that cause autism, but how these mutations lead to cortical dysfunction is not understood. Mutations in the gene phosphatase and tensin homolog on chromosome ten (PTEN) cause autism and intellectual disability. We have discovered that single-copy deletion of Pten results in overexpression of the small-conductance calcium-activated potassium channel in cortical neurons. This overexpression leads to decreased sensitivity of cortical neurons to incoming inputs. In vivo, this diminished excitability leads to decreased primary visual cortical responsiveness to visual stimuli. We hypothesize that diminished cortical responses in primary sensory regions lead to poor recruitment of secondary sensory cortices, leading to sensory processing deficits. Our findings identify a unique target for potential pharmacological intervention.

Abstract

De novo phosphatase and tensin homolog on chromosome ten (PTEN) mutations are a cause of sporadic autism. How single-copy loss of PTEN alters neural function is not understood. Here we report that Pten haploinsufficiency increases the expression of small-conductance calcium-activated potassium channels. The resultant augmentation of this conductance increases the amplitude of the afterspike hyperpolarization, causing a decrease in intrinsic excitability. In vivo, this change in intrinsic excitability reduces evoked firing rates of cortical pyramidal neurons but does not alter receptive field tuning. The decreased in vivo firing rate is not associated with deficits in the dendritic integration of synaptic input or with changes in dendritic complexity. These findings identify calcium-activated potassium channelopathy as a cause of cortical dysfunction in the PTEN model of autism and provide potential molecular therapeutic targets.

  • gain
  • visual cortex
  • SK
  • mTOR
  • sensory processing

Footnotes

  • ↵1P.G.-J.-C. and D.K.C. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. E-mail: pgolshani{at}mednet.ucla.edu.
  • Author contributions: P.G.-J.-C., D.K.C., J.T.T., and P.G. designed research; P.G.-J.-C., D.K.C., E.T., M.T.L., J.T.T., and P.G. performed research; P.G.-J.-C., D.K.C., E.T., M.T.L., J.T.T., and P.G. analyzed data; and P.G.-J.-C., D.K.C., J.T.T., and P.G. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission. B.S. is a guest editor invited by the Editorial Board.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1309207110/-/DCSupplemental.

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SK channelopathy in the PTEN model of autism
Pablo Garcia-Junco-Clemente, David K. Chow, Elaine Tring, Maria T. Lazaro, Joshua T. Trachtenberg, Peyman Golshani
Proceedings of the National Academy of Sciences Oct 2013, 201309207; DOI: 10.1073/pnas.1309207110

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SK channelopathy in the PTEN model of autism
Pablo Garcia-Junco-Clemente, David K. Chow, Elaine Tring, Maria T. Lazaro, Joshua T. Trachtenberg, Peyman Golshani
Proceedings of the National Academy of Sciences Oct 2013, 201309207; DOI: 10.1073/pnas.1309207110
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