The long-term goal of our group is to identify therapeutic targets in autism spectrum disorders (ASDs) and this proposal will focus on SHANK3 where it has been shown that deletions and mutations lead to ASDs. The overall objective of the proposal is to identify therapeutic targets for SHANK3-haploinsufficiency and our central hypothesis is that haploinsufficiency of SHANK3 leads to alterations in synapse development, glutamate transmission and synaptic plasticity in vivo that lead to observable behavioral phenotypes. The rationale for this proposal is that as we begin to understand the molecular, cellular, and regional impact of SHANK3 haploinsufficiency in vivo, we will have new targets that can form the basis of novel therapies for ASDs and associated disorders.
In Aim 1, we will measure excitatory synaptic function in Shank3-deficient mice by electrophysiology and synaptic biochemistry.
In Aim 2, we will quantify neuronal morphology and synapse structure and density in these animals.
In Aim 3, we will access social and learning and memory behaviors in the Shank3-deficient mice.
In Aim 4 will assess research compounds for effects in the mice using molecular deficits in synapses (Aim 1) to define targets for experimental interventions, with electrophysiological (Aim 1), morphological (Aim 2), and behavioral changes (Aim 3) as endpoints to assess the efficacy of a given intervention. The studies are significant because they represent a first step towards ultimate therapies for SHANK3-haploinsufficiency syndromes in that they will (a) identity molecular targets for therapies and (b) define preclinical outcome measures to be used for the assessment of novel therapeutics. In addition, as SHANK3 is such a central player in the synapse, these studies will also advance our understanding of the basic neurobiology of the synapse. The studies will also provide important data on the molecular, cellular and network components that underlie cognition and social behaviors. The proposed research is innovative, in our opinion, because it for the first time makes use of Shank3-deficient mice to study Shank3 function in situ, as a model for SHANK3-haploinsufficiency.

Public Health Relevance

The proposed research is relevant to public health and to the NIH mission because the studies will lead to a molecular and systems level understanding of Shank3 function and will identify molecular targets for novel therapeutics in human SHANK3-haploinsufficiency and in autism spectrum disorders. In addition, these studies will advance our understanding of the basic neurobiology of the synapse and of brain components that underlie cognition and social behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH093725-01
Application #
8084397
Study Section
Special Emphasis Panel (ZRG1-BDCN-W (02))
Program Officer
Asanuma, Chiiko
Project Start
2011-04-20
Project End
2016-03-31
Budget Start
2011-04-20
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$483,773
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Mitchell, A C; Javidfar, B; Pothula, V et al. (2018) MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice. Mol Psychiatry 23:123-132
Bryois, Julien; Garrett, Melanie E; Song, Lingyun et al. (2018) Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia. Nat Commun 9:3121
Fazio, Leonardo; Pergola, Giulio; Papalino, Marco et al. (2018) Transcriptomic context of DRD1 is associated with prefrontal activity and behavior during working memory. Proc Natl Acad Sci U S A 115:5582-5587
Gusev, Alexander; Mancuso, Nicholas; Won, Hyejung et al. (2018) Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet 50:538-548
Golden, Carla Em; Buxbaum, Joseph D; De Rubeis, Silvia (2018) Disrupted circuits in mouse models of autism spectrum disorder and intellectual disability. Curr Opin Neurobiol 48:106-112
Gandal, Michael J; Zhang, Pan; Hadjimichael, Evi et al. (2018) Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science 362:
Girdhar, Kiran; Hoffman, Gabriel E; Jiang, Yan et al. (2018) Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome. Nat Neurosci 21:1126-1136
Hauberg, Mads E; Fullard, John F; Zhu, Lingxue et al. (2018) Differential activity of transcribed enhancers in the prefrontal cortex of 537 cases with schizophrenia and controls. Mol Psychiatry :
Agrawal, A; Chou, Y-L; Carey, C E et al. (2018) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry 23:1293-1302
Curtis, David (2018) Polygenic risk score for schizophrenia is not strongly associated with the expression of specific genes or gene sets. Psychiatr Genet 28:59-65

Showing the most recent 10 out of 36 publications