Posted December 11, 2014
David H. Gutmann, M.D., Ph.D., Washington University
Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders affecting the nervous system. Neurocognitive impairments, including deficits in attention, function, language, and visual perception, have been reported in as many as two-thirds of children with NF1. Furthermore, these children are prone to peripheral nerve sheath tumors and brain tumors, such as optic gliomas, and treatment of these tumors can result in additional cognitive impairments. Several mouse models of NF1-associated tumors have been recently developed, although few studies have focused on the behavioral abnormalities. Dr. David Gutmann at Washington University has developed an Nf1 genetically-engineered mouse (GEM) model of optic glioma in order to study learning and behavioral abnormalities and to test potential therapies that may improve these abnormalities.
With support from a Fiscal Year 2009 (FY09) Neurofibromatosis Research Program (NFRP) Investigator-Initiated Research Award, Dr. Gutmann and his research team developed behavioral tests to analyze NF1-associated behavioral abnormalities in mice. Through this effort, he found that these Nf1 GEM strains display cognitive impairments that mirror those seen in children with NF1, including abnormal exploratory behaviors and spatial learning and memory deficits. Upon investigation into the causal mechanism(s) underlying these abnormalities, Dr. Gutmann discovered that reduced brain dopamine levels are responsible for these deficits. Leveraging these findings, they used an imaging technique called [11C]-raclopride positron emission tomography (PET) to quantify levels of dopamine in these mice compared to control mice. In addition, they found that lower dopamine levels in the hippocampus cause the learning and memory deficits in these mice. Interestingly, Dr. Gutmann demonstrated that male, but not female, Nf1 GEM exhibited problems with spatial learning and memory, reflecting male-specific differences in hippocampal dopamine levels.
The exciting connection between dopamine reduction and neurocognitive abnormalities provides further preclinical evidence for testing agents that increase dopamine levels in the brain. To explore this possibility in mice, Dr. Gutmann utilized known dopamine-restorative agents, such as methylphenidate (Ritalin), L-Deprenyl (Selegiline), and the dopamine precursor L-DOPA, to demonstrate that these drugs improved the learning and exploratory deficits, and restored dopamine levels as measured by PET imaging.
The neurocognitive assessments in Nf1 GEM strains by Dr. Gutmann's research team have provided important insights into the behavioral abnormalities that occur in children with NF1, and support the use of dopamine-restorative agents to improve these defects. Furthermore, Dr. Gutmann has determined that these neurocognitive defects and dopamine signaling dysfunction are sex-dependent in mice, suggesting that sex may be an important prognostic factor for the neurocognitive impairments in children with NF1. These results also highlight the ability of Nf1 GEM strains to serve as platforms for the discovery, development and testing of drugs to improve these cognitive and behavioral defects.
Additionally, Dr. Gutmann has identified that optic gliomas forming in Nf1 GEM strains are composed of both cancerous and non-cancerous cell types. This observation set the foundation for an FY12 NFRP Investigator-Initiated Research Award, in which Dr. Gutmann plans to further characterize the optic glioma cell types in order to identify improved, less toxic therapies for NF1 optic gliomas. With this new award, Dr. Gutmann hopes to better understand why optic gliomas form and how we might develop therapies that target not only the cancerous cells in the tumor, but also those non-cancerous cells that support optic glioma growth.
Raclopride PET imaging reveals increased binding in the Nf1 GEM strain (CKO) indicative of lower dopamine levels relative to control wild-type (WT) mice.
Brown JA, Xu J, Diggs-Andrews KA, Wozniak DF, Mach RH, Gutmann, DH. 2011. PET imaging for attention deficit preclinical drug testing in neurofibromatosis-1 mice. Exp Neurol 232(2):333-338.
Gutmann DH, Parada LF, Silva AJ, Ratner N. 2012. Neurofibromatosis type 1: modeling CNS dysfunction. J Neurosci 110:1-7.
Diggs-Andrews KA and Gutmann DH. 2013. Modeling cognitive dysfunction in neurofibromatosis-1. Trends Neurosci 36(4):237-247.
Wozniak DF, Diggs-Andrews KA, Conyers S, Yuede CM, Dearborn JT, Brown JA, Tokuda K, Izumi Y, Zorumski CF, Gutmann DH. 2013. Motivational disturbances and effects of L-dopa administration in neurofibromatosis-1 model mice. PLoS One 8:e66024.
Diggs-Andrews KA, Tokuda K, Izumu Y, Zorumski CF, Wozniask DF, Gutmann DH. 2013. Dopamine deficiency underlies learning deficits in neurofibromatosis-1 mice. Ann Neurol 73(2):309-315.
Diggs-Andrews KA, Brown JA, Gianino SM, Rubin JB, Wozniak DF, Gutmann DH. 2014. Sex is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann Neurol 75(2):309-316.