Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Carrie Shilyansky, Katherine H. Karlsgodt, Damian M. Cummings, Kyriaki Sidiropoulou, Molly Hardt, Alex S. James, Dan Ehninger, Carrie E. Bearden, Panayiota Poirazi, J. David Jentsch, Tyrone D. Cannon, Michael S. Levine, and Alcino J. Silva
PNAS July 20, 2010 107 (29) 13141-13146; https://doi.org/10.1073/pnas.1004829107

  1. Edited* by Richard F. Thompson, University of Southern California, Los Angeles, CA, and approved June 1, 2010 (received for review April 14, 2010)

Abstract

Neurofibromatosis type I (NF1) is one of the most common single-gene causes of learning disabilities. Here, we use behavioral working memory probes and electrophysiological studies in a mouse model of NF1 (Nf1 heterozygous null mutants; Nf1+/−) to demonstrate that (i) Neurofibromin regulates prefrontal and striatal inhibitory networks, specifically activity-dependent GABA release and (ii) is required for working memory performance, with inhibition-dependent working memory deficits seen in Nf1+/− mice. We find that increased inhibition in medial prefrontal cortex (mPFC) is sufficient to alter persistent activity in a biophysical model of an mPFC microcircuit, suggesting a possible mechanism for Nf1+/− working memory deficits. Accordingly, working memory assays applied during functional MRI (fMRI) studies in human subjects with NF1 reveal hypoactivation of corticostriatal networks, which is associated with impaired working memory performance. Collectively, these integrative mouse and human studies reveal molecular and cellular mechanisms contributing to working memory deficits in NF1.

Footnotes

  • 1To whom correspondence should be addressed. E-mail: silvaa{at}mednet.ucla.edu.

  • Author contributions: C.S., K.H.K., D.M.C., A.S.J., D.E., P.P., J.D.J., T.D.C., M.S.L., and A.J.S. designed research; C.S., K.H.K., D.M.C., K.S., and M.H. performed research; C.S., K.H.K., D.M.C., K.S., A.S.J., C.E.B., P.P., J.D.J., M.S.L., and A.J.S. analyzed data; and C.S., K.H.K., C.E.B., J.D.J., M.S.L., and A.J.S. wrote the paper.

  • The authors declare no conflict of interest.

  • ↵*This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1004829107/-/DCSupplemental.

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    Neurofibromin regulates corticostriatal inhibitory networks during working memory performance
    Carrie Shilyansky, Katherine H. Karlsgodt, Damian M. Cummings, Kyriaki Sidiropoulou, Molly Hardt, Alex S. James, Dan Ehninger, Carrie E. Bearden, Panayiota Poirazi, J. David Jentsch, Tyrone D. Cannon, Michael S. Levine, Alcino J. Silva
    Proceedings of the National Academy of Sciences Jul 2010, 107 (29) 13141-13146; DOI: 10.1073/pnas.1004829107
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