Diverse genetic mutations cause different neurodevelopmental disorders, yet many syndromes share similar intellectual impairments. The overarching aim of this multidisciplinary project, enabled by specific expertise from three principal investigators, is to discover fundamental mechanisms responsible for cognitive impairments across genetic mouse models of diverse neurodevelopmental disorders. We hypothesize that various upstream genetic abnormalities converge on common downstream mechanisms to produce learning disabilities across syndromes. Synaptic activation of small GTPases drives remodeling of the dendritic spine actin cytoskeleton, a far-downstream mechanism which underlies enduring synaptic plasticity, learning and memory. We will test the hypothesis that failure to properly reorganize the subsynaptic cytoskeleton is a shared endpoint across neurodevelopmental disorders, employing established mouse models of Fragile X (Fmr1), Rett (Mecp2), Down (Ts65Dn) and Angelman (Ube3a) syndromes.
Aim 1 will use theta burst stimulation and three learning paradigms to test the hypothesis that the four mutant lines all exhibit deficits in synaptic GTPase activation and actin remodeling in cortex and hippocampus. We further propose that normalizing these signaling dysfunctions will restore cognitive functions. Our preliminary data indicate that changing the spacing of afferent activity rescues hippocampal long-term potentiation (LTP), and changing the spacing of cognitive training rescues one form of learning.
Aim 2 will test the hypotheses that newly identified timing rules for LTP will engage the impaired actin regulatory cascades and facilitate synaptic potentiation in the mutants, and that analogous spaced training regimens in three different cognitive tasks will restore synaptic GTPase activation and learning. We discovered that impairments in actin regulation, LTP and learning in Fmr1 and Ube3a mice are rescued by increasing the availability of BDNF, which facilitates signaling to restore actin stabilization. Ai 3 will employ these same downstream endpoints for preclinical evaluation of pharmacological rescues. Two compounds that lower the threshold for GTPase activation in the wildtypes will be tested for efficacy in (1) reversing defects in signaling leading to actin stabilization, (2) restoing LTP, and (3) improving cognitive performance in the four models. Investigations of novel, broad spectrum behavioral and pharmacological interventions which enhance the activation of downstream mechanisms, and which can be readily implemented clinically, will address a fundamental neurobiological hypothesis with unifying translational implications for improving cognitive abilities in multiple neurodevelopmental disorders.

Public Health Relevance

Neurodevelopmental disorders with severe intellectual disabilities represent an unmet medical need with high financial costs to the U.S. educational and health care systems, as well as emotional, economic and practical challenges to families. While a wide range of therapeutic strategies have been proposed, and several are in early clinical trials, none has yet successfully treated the defining cognitive impairments in disorders such as Fragile X, Rett, Down and Angelman syndromes. Using genetic mouse models of these four disorders, we will test the hypothesis that a distinct cascade of molecular events converges on one common final biological pathway, actin stabilization, required for functional synaptic plasticity in the connections between neurons. Translational elements of the project harness these potential biomarkers of actin signaling required for lasting synaptic modification, to discover novel, broad spectrum therapeutics with immediate clinical potential for improving cognitive abilities in multiple neurodevelopmental disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS085709-03
Application #
8850008
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Mamounas, Laura
Project Start
2013-09-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Davis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Wang, Weisheng; Le, Aliza A; Hou, Bowen et al. (2018) Memory-Related Synaptic Plasticity Is Sexually Dimorphic in Rodent Hippocampus. J Neurosci 38:7935-7951
Stoppel, Laura J; Kazdoba, Tatiana M; Schaffler, Melanie D et al. (2018) R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice. Neuropsychopharmacology 43:513-524
Leach, P T; Crawley, J N (2018) Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities. Genes Brain Behav 17:e12452
Gulinello, Maria; Mitchell, Heather A; Chang, Qiang et al. (2018) Rigor and reproducibility in rodent behavioral research. Neurobiol Learn Mem :
López, Alberto J; Jia, Yousheng; White, André O et al. (2018) Medial habenula cholinergic signaling regulates cocaine-associated relapse-like behavior. Addict Biol :
Wang, W; Cox, B M; Jia, Y et al. (2018) Treating a novel plasticity defect rescues episodic memory in Fragile X model mice. Mol Psychiatry 23:1798-1806
Sukoff Rizzo, Stacey J; Crawley, Jacqueline N (2017) Behavioral Phenotyping Assays for Genetic Mouse Models of Neurodevelopmental, Neurodegenerative, and Psychiatric Disorders. Annu Rev Anim Biosci 5:371-389
Gompers, Andrea L; Su-Feher, Linda; Ellegood, Jacob et al. (2017) Germline Chd8 haploinsufficiency alters brain development in mouse. Nat Neurosci 20:1062-1073
Vogel Ciernia, Annie; Pride, Michael C; Durbin-Johnson, Blythe et al. (2017) Early motor phenotype detection in a female mouse model of Rett syndrome is improved by cross-fostering. Hum Mol Genet 26:1839-1854
Pearson, Brandon L; Crawley, Jacqueline N; Eilam, David et al. (2017) Curiosity as an approach to ethoexperimental analysis: Behavioral neuroscience as seen by students and colleagues of Bob Blanchard. Neurosci Biobehav Rev 76:415-422

Showing the most recent 10 out of 19 publications