RT Journal Article
SR Electronic
T1 Disruption of Critical Period Plasticity in a Mouse Model of Neurofibromatosis Type 1
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 5495
OP 5509
DO 10.1523/JNEUROSCI.2235-19.2020
VO 40
IS 28
A1 Mariska van Lier
A1 M. Hadi Saiepour
A1 Koen Kole
A1 Juliette E. Cheyne
A1 Nawal Zabouri
A1 Thomas Blok
A1 Yi Qin
A1 Emma Ruimschotel
A1 J. Alexander Heimel
A1 Christian Lohmann
A1 Christiaan N. Levelt
YR 2020
UL http://www.jneurosci.org/content/40/28/5495.abstract
AB Neurofibromatosis type 1 (NF1) is a common monogenic neurodevelopmental disorder associated with physical and cognitive problems. The cognitive issues are thought to arise from increased release of the neurotransmitter GABA. Modulating the signaling pathways causing increased GABA release in a mouse model of NF1 reverts deficits in hippocampal learning. However, clinical trials based on these approaches have so far been unsuccessful. We therefore used a combination of slice electrophysiology, in vivo two-photon calcium imaging, and optical imaging of intrinsic signal in a mouse model of NF1 to investigate whether cortical development is affected in NF1, possibly causing lifelong consequences that cannot be rescued by reducing inhibition later in life. We find that, in NF1 mice of both sexes, inhibition increases strongly during the development of the visual cortex and remains high. While this increase in cortical inhibition does not affect spontaneous cortical activity patterns during early cortical development, the critical period for ocular dominance plasticity is shortened in NF1 mice due to its early closure but unaltered onset. Notably, after environmental enrichment, differences in inhibitory innervation and ocular dominance plasticity between NF1 mice and WT littermates disappear. These results provide the first evidence for critical period dysregulation in NF1 and suggest that treatments aimed at normalizing levels of inhibition will need to start at early stages of development.SIGNIFICANCE STATEMENT Neurofibromatosis type 1 is associated with cognitive problems for which no treatment is currently available. This study shows that, in a mouse model of neurofibromatosis type 1, cortical inhibition is increased during development and critical period regulation is disturbed. Rearing the mice in an environment that stimulates cognitive function overcomes these deficits. These results uncover critical period dysregulation as a novel mechanism in the pathogenesis of neurofibromatosis type 1. This suggests that targeting the affected signaling pathways in neurofibromatosis type 1 for the treatment of cognitive disabilities may have to start at a much younger age than has so far been tested in clinical trials.