Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Carrie Shilyansky(University of California, Los Angeles), Katherine H. Karlsgodt(University of California, Los Angeles), Damian M. Cummings(University of California, Los Angeles), Kyriaki Sidiropoulou(Foundation for Research and Technology Hellas), Molly Hardt(University of California, Los Angeles), Alex S. James(University of California, Los Angeles), Dan Ehninger(University of California, Los Angeles), Carrie E. Bearden(University of California, Los Angeles), Panayiota Poirazi(Foundation for Research and Technology Hellas), J. David Jentsch(University of California, Los Angeles), Tyrone D. Cannon(University of California, Los Angeles), Michael S. Levine(University of California, Los Angeles), Alcino J. Silva(University of California, Los Angeles)
Proceedings of the National Academy of Sciences
July 12, 2010
10.1073/pnas.1004829107
Cited by 168Open Access
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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.

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