Molecular control of developing corticostriatal circuits and behaviors in an autism model
2017 Weatherstone Predoctoral Fellowship
New York, New York
Autism spectrum disorder is associated with dysfunctional corticostriatal networks. Molecular control over development of these connections remains to be defined. Research has implicated rare microdeletions in the gene encoding the trans-synaptic adhesion protein cadherin-8 (Cdh8) in ASD. Cdh8 is expressed in prefrontal cortex and striatum during early postnatal corticostriatal synaptogenesis.
We hypothesize that deficits in molecular control of developing corticostriatal synaptic circuitry by Cdh8 may contribute to autism. To test this, we generated conditional Cdh8 knockout (KO) mice. In our proposed project, I will selectively delete Cdh8 from striatal and/or cortical neurons early in postnatal development.
In Aim 1 of the proposed study, I will study the effects of Cdh8 ablation on anatomical development of the corticostriatal projection by combining axonal tracing, immunocytochemistry and cleared-brain techniques (iDISCO).
In Aim 2, I will study the effects of Cdh8 deletion on corticostriatal synaptic function and plasticity using whole-cell voltage clamp recordings from striatal neurons.
In Aim 3, I will test young adult Cdh8 KO and control mice on behavioral tasks that model deficits in cognitive flexibility, attention, 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. These studies target neuroscience, genetics and translational research areas.
Grant Term:2 years
Award Type:Weatherstone Predoctoral Fellowship