Neurofibromin regulates corticostriatal inhibitory networks during working memory performance.

TitleNeurofibromin regulates corticostriatal inhibitory networks during working memory performance.
Publication TypeJournal Article
Year of Publication2010
AuthorsShilyansky, C, Karlsgodt KH, Cummings DM, Sidiropoulou K, Hardt M, James AS, Ehninger D, Bearden CE, Poirazi P, Jentsch DJ, Cannon TD, Levine MS, Silva AJ
JournalProceedings of the National Academy of Sciences of the United States of America
Date Published2010 Jul 20
KeywordsAnimals, Behavior, Animal, Computer Simulation, Excitatory Postsynaptic Potentials, Female, gamma-Aminobutyric Acid, Humans, Inhibitory Postsynaptic Potentials, Male, Memory, Short-Term, Mice, Models, Biological, Neostriatum, Neural Inhibition, Neurofibromatosis 1, Neurofibromin 1, Prefrontal Cortex, ras Proteins, Signal Transduction, Young Adult

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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.