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 finetuning and plasticity of developing functional synaptic connectivity. We have shown that mRNA encoding cadherin8 (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, electrophysiology and behavioral assessment. The vertical integration across these objectives (spanning molecules, synapses, circuits and behaviors) will provide novel insight into molecular control of brain pathways implicated in cognitive and behavioral 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.
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 and obsessive compulsive disorders, disorders that are associated with abnormal synaptic function, plasticity, and cognitive abilities that depend on corticostriatal information processing
|Matikainen-Ankney, Bridget A; Kezunovic, Nebojsa; Menard, Caroline et al. (2018) Parkinson's Disease-Linked LRRK2-G2019S Mutation Alters Synaptic Plasticity and Promotes Resilience to Chronic Social Stress in Young Adulthood. J Neurosci 38:9700-9711|
|Benson, Deanna L; Matikainen-Ankney, Bridget A; Hussein, Ayan et al. (2018) Functional and behavioral consequences of Parkinson's disease-associated LRRK2-G2019S mutation. Biochem Soc Trans 46:1697-1705|
|Ibi, Daisuke; de la Fuente Revenga, Mario; Kezunovic, Nebojsa et al. (2017) Antipsychotic-induced Hdac2 transcription via NF-?B leads to synaptic and cognitive side effects. Nat Neurosci 20:1247-1259|