Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13141-6. doi: 10.1073/pnas.1004829107. Epub 2010 Jul 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Computer Simulation
  • Excitatory Postsynaptic Potentials / physiology
  • Female
  • Humans
  • Inhibitory Postsynaptic Potentials / physiology
  • Male
  • Memory, Short-Term / physiology*
  • Mice
  • Models, Biological
  • Neostriatum / metabolism*
  • Neostriatum / physiopathology
  • Neural Inhibition / physiology*
  • Neurofibromatosis 1 / physiopathology
  • Neurofibromin 1 / deficiency
  • Neurofibromin 1 / metabolism*
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiopathology
  • Signal Transduction
  • Young Adult
  • gamma-Aminobutyric Acid / metabolism
  • ras Proteins / metabolism


  • Neurofibromin 1
  • gamma-Aminobutyric Acid
  • ras Proteins