Autism Spectrum Disorders (ASDs) comprise a range of neurodevelopmental abnormalities in cognitive abilities and behaviors associated with dysfunctional circuitry between the prefrontal cortex (PFC) and the neostriatum. Behavioral abnormalities emerge early after birth and are thought to reflect defects in the fine- tuning and plasticity of developing functional synaptic connectivity. We have observed that mRNA encoding cadherin-8 (Cdh8)-a type II, synaptically-localized classic cadherin-is highly enriched in PFC and dorsal striatum during early postnatal development. Moreover, the timing, anatomical distribution, and axon targeting function of Cdh8 suggest strongly that Cdh8 may be crucial for the development and plasticity of PFC->striatal circuitry. This is significant because several recent studies have linked Cdh8 genetically to susceptibility to ASDs. Thus, we hypothesize that cognitive ASD-like phenotypes reflect impaired synaptic development of PFC->striatal direct- and/or indirect-pathway circuitry due to deficient Cdh8-dependent molecular control over these pathways. We will test this hypothesis by combining mouse genetics, anatomy, and electrophysiology. The vertical integration across these objectives (spanning molecules, synapses and circuits) will provide novel insight into molecular control of brain pathways implicated in cognitive deficits associated with ASDs. This is important, because corticostriatal circuit defects are central to a number of aberrant behaviors associated with autism and anxiety disorders, but there is surprisingly little known about the normal development and plasticity of such circuits.

Public Health Relevance

A more detailed understanding of how cell adhesion molecules regulate development and function of prefrontal cortex ->striatal circuitry in brain wil provide novel insight into the molecular control of information flow through discrete cortical-striatal networks. Abnormal information processing through such networks, when compromised, underlie a variety of neurological and psychiatric diseases including autism spectrum disorders, a disorder that is associated with abnormal synaptic function, plasticity, and cognitive abilities that depend on cortical-striatal information processing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH100600-01A1
Application #
8638333
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Asanuma, Chiiko
Project Start
2014-03-18
Project End
2016-02-28
Budget Start
2014-03-18
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$254,250
Indirect Cost
$104,250
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
Friedman, Lauren G; Riemslagh, Fr├ęderike W; Sullivan, Josefa M et al. (2015) Cadherin-8 expression, synaptic localization, and molecular control of neuronal form in prefrontal corticostriatal circuits. J Comp Neurol 523:75-92