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PMID: 20624961 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 107 ·No. 29 ·2010-07-20 ·Pages 13141-6

Shilyansky C, Karlsgodt KH, Cummings DM, Sidiropoulou K, Hardt M, James AS, Ehninger D, Bearden CE, Poirazi P, Jentsch JD, Cannon TD, Levine MS, Silva AJ

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.

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,physiopathology Neural Inhibition/physiology Neurofibromatosis 1/physiopathology Neurofibromin 1/deficiency,metabolism Prefrontal Cortex/metabolism,physiopathology Signal Transduction Young Adult gamma-Aminobutyric Acid/metabolism ras Proteins/metabolism
Chemicals
Neurofibromin 1 gamma-Aminobutyric Acid ras Proteins
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Shilyansky Carrie
Department of Neurobiology, University of California, Los Angeles, CA 90095, USA.
Karlsgodt Katherine H
Cummings Damian M
Sidiropoulou Kyriaki
Hardt Molly
James Alex S
Ehninger Dan
Bearden Carrie E
Poirazi Panayiota
Jentsch J David
Cannon Tyrone D
Levine Michael S
Silva Alcino J
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1004829107
Published
2010-07-20
Epub
2010-00-12
Pages
13141-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2919968
Subset
IM
Grants
NIMH NIH HHS · T32 MH019384 · United States
NIMH NIH HHS · R01 MH084315 · United States
NIMH NIH HHS · 2T32MH019384-11A2 · United States
NIMH NIH HHS · R34 MH089299 · United States
NIMH NIH HHS · 2 R01 MH084315-10 · United States
NIMH NIH HHS · R34 MH089299-01 · United States
External Links
PubMed source DOI: 10.1073/pnas.1004829107 PMC Full Text View journal details
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