Autism Spectrum Disorders (ASDs) are associated with dysfunctional corticostriatal networks. Molecular control over development of these connections remains to be defined. Rare microdeletions in the gene encoding the transsynaptic adhesion protein cadherin-8 (Cdh8) are implicated in ASDs. Cdh8 is expressed in prefrontal cortex and striatum during early postnatal corticostriatal synaptogenesis. We hypothesize that deficits in Cdh8-dependent control of developing corticostriatal synaptic circuitry contributes to autism-related behaviors. To test this, we generated conditional Cdh8 knockout (cKO) mice where I will selectively delete Cdh8 from striatal and/or cortical neurons early in postnatal development.
In Aim 1, the effects of Cdh8 ablation on neuronal connectivity and synaptic plasticity of pre-and post-synaptic corticostriatal neuronal populations will be studied by combining axonal tracing, whole-cell recording approaches and morphometric analyses.
In Aim 2, young adult Cdh8 cKO and control mice will be tested on behavioral tasks that model deficits in cognitive flexibility, social contact and perseverative/obsessive behaviors observed in autism. We expect significant deficits in corticostriatal connectivity and synaptic function leading to impairments in striatally-based behaviors. Together, this project will reveal new details about normal corticostriatal development, as well as identify potential molecular mechanisms that could become targets for therapeutic treatment in ASDs.

Public Health Relevance

Autism Spectrum Disorders (ASDs) are a set of heterogeneous neurodevelopmental disorders characterized by cognitive, behavioral and perseverative motor abnormalities affecting about 1 in 68 children nationwide. Recent genome-wide association studies found that rare a microdeletion in chromosome 16 which encodes for a single gene, Cadherin-8 (Cdh8), is associated with autism and learning disabilities. This proposal aims to evaluate the effects of Cdh8 deletion in early life on the development of corticostriatal circuits and the behaviors supported by such circuits that become abnormal with autism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH115541-03
Application #
9930156
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Van'T Veer, Ashlee V
Project Start
2018-06-15
Project End
2020-12-14
Budget Start
2020-06-15
Budget End
2020-12-14
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029