Indiana University-Purdue University Indianapolis (IUPUI) / Nearly 18% of children are diagnosed with developmental disabilities. Autism
spectrum disorders (ASDs) and attention deficit hyperactivity disorder (ADHD) are
increasingly common developmental disabilities, but neither is well understood. ADHD
and ASD are both prevalent in the genetic disorder Neurofibromatosis type 1 (NF1)
which impairs the Ras-MAPK/ERK pathway through mutation of the neurofibromin gene
(NF1+/−). More broadly, syndromic forms of developmental disorders are often caused by
mutations of proteins in pathways interconnected with Ras including TSC1/2, FMR1, and
SynGAP. Of NF1 patients, around 30-50% are diagnosed with ASDs and more than 60%
with ADHD.
These studies are the first to show that male mice haploinsufficient for the Nf1
gene (Nf1+/−) exhibit deficits in behavioral inhibition in multiple contexts, a key feature
of ADHD. They exhibit hyperactivity and impulsivity in an open field, delay discounting
task, and cliff avoidance reaction test, rescuable through treatment with the clinically
effective ADHD drug, guanfacine (α2A adrenergic receptor agonist). Previous
experiments in our lab identified social deficits including deficits in consolidation of
social memory. Using optogenetics and awake behaving electrode recordings, we
explored the role of the cortico-striatal-limbic circuitry in impulsivity and in social deficits in male Nf1+/− mice. Manipulation of the prefrontal cortex, nucleus accumbens,
or basolateral amygdala through optogenetics rescued social deficits. These studies are
the first to record brain activity in a preclinical model of NF1 during impulsive behavior,
finding broad spectrum changes across slow, delta, theta, and gamma oscillatory
frequencies and decreased synchrony of the prefrontal cortex and nucleus accumbens
during a delay discounting task. Overall, Nf1+/− male mice with deletion of a single NF1
gene recapitulate cognitive phenotypes of NF1 patients and are a useful model system to
identify alterations in neural circuitry associated with ASD and ADHD.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/29302 |
| Date | 05 1900 |
| Creators | Drozd, Hayley Paulina |
| Contributors | McKinzie, David L., Clapp, D. Wade, Shekhar, Anantha, Lukkes, Jodi L., Lapish, Christopher L., Block, Michelle L. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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