The focus of this revised competitive renewal is to understand the neurobiological substrates that link single gene mutations to cognitive deficits. Currently, there is no effective treatment for the cognitive disruptions that define neurodevelopmental disorders (NDDs). In order to develop therapeutic strategies that improve the lives of affected individuals, it is imperative to understand how the neurobiological substrates that underlie reduced cognition and behavioral adaptations are damaged in these disorders. Our work during the last budget period established Syngap1 Heterozygous KO mice as a robust model that will advance our understanding of how cognitive and behavioral disruptions arise in NDDs. In particular, we established that pathogenic Syngap1 mutations damage the developing brain by altering the maturation rate of forebrain excitatory neurons. We also succeeded in connecting alterations to forebrain pyramidal neuron maturation in Syngap1 mutant mice to reduced cognitive ability. However, it remains unclear how altered neuronal maturation actually degrades cognitive ability. Our studies in this revised proposal are designed to explore the hypothesis that there is a spatial pattern of circuit assembly errors in Syngap1 mutants. We believe that alternated maturation of forebrain pyramidal neurons disrupts the assembly of cortical circuits that underlies cognitive ability, which is hypothesized to be a key neurobiological substrate that connects pathogenic Syngap1 mutations to altered cognition. The impact of our expected results is that the pattern of circuit assembly errors could define the particular cognitive endophenotype displayed by Syngap1 mutant mice, which would provide significant insight into the etiology of reduced cognition due to a single gene disruption. In addition, the patterns of assembly errors in Syngap1 mutants could be used as a comparative benchmark to understand similarities and/or differences in patterns of altered circuitry in other monogenic forms of NDDs. The long-term goal of this proposal is to identify the cells in the brain that are most severely impacted by pathogenic Syngap1 mutations. Once we understand the cellular origins of the disorder, we will have a much better entry point for gaining insight into te molecular perturbations that trigger the systems level dysfunction that directly leads to reduced cognitive ability. At the conclusion of the next requested budget period, we believe we will have reduced this disorder down to a relatively selective pool of neurons that are particularly sensitiv to pathogenic Syngap1 mutations. When this information is combined with the critical period information discovered in the previous budget period, we will have the ideal entry point for assessing how pathogenic Synagp1 mutations disrupt the molecular pathways that control growth and maturation of developing forebrain pyramidal neurons. In the subsequent budget period, we would then begin studying how altered developmental Syngap1 expression in this pool of neurons triggers changes in neuronal maturation.

Public Health Relevance

Presently, there is no cure for Intellectual Disability (ID) or Autism Spectrum Disorder (ASD). This proposal outlines experiments designed to understand how a gene that causes ID and increases the risk of developing epilepsy and/or ASD functions during development to promote the emergence of life-long cognitive ability.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (57))
Program Officer
Talley, Edmund M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Florida
United States
Zip Code
Kilinc, Murat; Creson, Thomas; Rojas, Camilo et al. (2018) Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders. Mol Cell Neurosci 91:140-150
Young, E J; Blouin, A M; Briggs, S B et al. (2016) Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use. Mol Psychiatry 21:615-23
Ogden, Kevin K; Ozkan, Emin D; Rumbaugh, Gavin (2016) Prioritizing the development of mouse models for childhood brain disorders. Neuropharmacology 100:2-16
Aceti, Massimiliano; Creson, Thomas K; Vaissiere, Thomas et al. (2015) Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly. Biol Psychiatry 77:805-15
Ozkan, Emin D; Aceti, Massimiliano; Creson, Thomas K et al. (2015) Input-specific regulation of hippocampal circuit maturation by non-muscle myosin IIB. J Neurochem 134:429-44
Zhou, Minghai; Ottenberg, Gregory; Sferrazza, Gian Franco et al. (2015) Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment. Brain 138:992-1008
Rumbaugh, Gavin; Sillivan, Stephanie E; Ozkan, Emin D et al. (2015) Pharmacological Selectivity Within Class I Histone Deacetylases Predicts Effects on Synaptic Function and Memory Rescue. Neuropsychopharmacology 40:2307-16
Young, Erica J; Aceti, Massimiliano; Griggs, Erica M et al. (2014) Selective, retrieval-independent disruption of methamphetamine-associated memory by actin depolymerization. Biol Psychiatry 75:96-104
Ozkan, Emin D; Creson, Thomas K; Kramár, Enikö A et al. (2014) Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons. Neuron 82:1317-33
Griggs, Erica M; Young, Erica J; Rumbaugh, Gavin et al. (2013) MicroRNA-182 regulates amygdala-dependent memory formation. J Neurosci 33:1734-40

Showing the most recent 10 out of 20 publications