Neurofibromin regulates corticostriatal inhibitory networks during working memory performance.
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.
Shilyansky
Carrie
C
Department of Neurobiology, University of California, Los Angeles, CA 90095, USA.
Karlsgodt
Katherine H
KH
Cummings
Damian M
DM
Sidiropoulou
Kyriaki
K
Hardt
Molly
M
James
Alex S
AS
Ehninger
Dan
D
Bearden
Carrie E
CE
Poirazi
Panayiota
P
Jentsch
J David
JD
Cannon
Tyrone D
TD
Levine
Michael S
MS
Silva
Alcino J
AJ
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003198:Computer Simulation; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D017072:Neostriatum / Q000378:metabolism* / Q000503:physiopathology; D009433:Neural Inhibition / Q000502:physiology*; D009456:Neurofibromatosis 1 / Q000503:physiopathology; D025542:Neurofibromin 1 / Q000172:deficiency / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D025542:Neurofibromin 1; D005680:gamma-Aminobutyric Acid; D018631:ras Proteins