A-ephrins in Neuropsychiatric Spectrum Disorder Models

Abstract

Neuropsychiatric spectrum disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are frequently comorbid and exhibit overlapping abnormalities in both behavioral symptoms and abnormalities in frontal corticostrialal circuits. Thus, it is a particular challenge to identify a "core" molecular pathogenesis that can differentiate between such disorders yet also account for the "spectrum nature" of their phenotypes (clinical presentations) and endophenotypes (underlying neurobiological dysfunction). Given the polygenic and multifactorial etiologies of neuropsychiatric spectrum disorders, there is a need to identify simplifying circuit-level concepts. One strategy proposed for this has been to consider circuit development as a fundamental unit for understanding behavior. This thesis adopted this approach by examining the effects on behavior and anatomy in striatal excitatory microcircuits of gene deletions of A-ephrins, a set of developmental patterning molecules with broad yet complex interactive effects on the development and plasticity of neural macrocircuits and synaptic microcircuits.

First, I tested the hypothesis that specific and combinatorial deletions of ephrin-A ligands are sufficient to generate complex behavioral phenotypes with cross-domain features characteristic of human neuropsychiatric disorders involving dysfunctional frontal-corticostriatal circuitry. Given behavioral evidence in support of this, I next examined dendritic spine morphology in sensorimotor and limbic regions of the striatum seeking evidence that the behavioral phenotype was specifically correlated with changes in frontostriatal circuitry associated with the functional domain of the abnormal behavior. As I did find regional differences in dendritic spine density within the striatum that were correlated with specific learning and memory deficits, I then investigated whether these were accompanied by physiological changes in cell membrane properties or synaptic activity in these striatal regions, and whether the morphological effects detected in adulthood alongside behavioral deficits were present at the much younger developmental age of mice in the electrophysiology experiments. Accordingly, I was able to associate behavioral phenotype with evidence of abnormalities at a circuitry level, but I determined that these effects were not manifest during postnatal development. This raises the possibility that these effects were downstream of general or specific dysfunction along these circuits and may have been experience-dependent.