Autism and ADHD in NF1: Insights from a Mouse Model

  • H.P. Drozd, B.S. IMPRS in the SRPinAM
  • J.L. Lukkes, PhD Deptartment of Psychiatry, Indiana University School of Medicine
  • A.R. Abreu, PhD Department of Pharmacology and Toxicology, Indiana University School of Medicine
  • E.T. Dustrude. PhD Deptartment of Psychiatry, Indiana University School of Medicine
  • Su-Jung Park, PhD Deptartment of Pediatrics, Indiana University School of Medicine
  • D. Wade Clapp, MD Deptartment of Pediatrics, Indiana University School of Medicine
  • A.I. Molosh Deptartment of Psychiatry, Indiana University School of Medicine
  • A. Shekhar, MD, PhD Indiana University School of Medicine

Abstract

Background and Hypothesis: Children with Neurofibromatosis type 1 (NF1) suffer from a significantly higher incidence of ADHD and Autism. Deletion of a single Nf1 allele (Nf1+/-) in mice is a well-established model of NF1 that recapitulates the peripheral tumors phenotype. We have shown that Nf1+/- mice demonstrate autism-like social and communication deficits and that increased activation of the Ras pathway in the basolateral amygdala (BLA) causes social deficits. We hypothesized that Nf1+/- mice will exhibit ADHD-like behaviors.
Experimental Design: To further test the role of BLA, we activated this region in WT mice or inhibited the BLA of Nf1+/- mice through optogenetic stimulation following acquisition of a social memory in the social preference test. Dual immunofluorescence was then used to map pERK activation and GFP expression in the BLA. In a second experiment, we examined impulsive choice in WT and Nf1+/- mice using a delayed discounting task.
Results: Long-term memory of WT mice was disrupted after optogenetic BLA stimulation and pERK expression in the BLA was increased in Experiment 1. In contrast, BLA inhibition of Nf1+/- mice did not rescue social learning deficits. In Experiment 2, Nf1+/- mice choose a higher percentage of smaller rewards when a 10 s and 20 s delay was administered compared to WT mice, suggesting Nf1+/- mice are more impulsive.
Conclusion and Potential Impact: These data provide the first genetic mouse model to study ADHD symptoms in NF1 patients and shed further light on the CNS pathways regulating autism-like deficits.

Published
2018-08-02
Section
Indiana Medical Student Program for Research and Scholarship Oral Presentations