Date of Completion

Spring 5-1-2017

Thesis Advisor(s)

Dr. R. Holly Fitch

Honors Major

Physiology and Neurobiology

Second Honors Major

Individualized Major

Disciplines

Behavioral Neurobiology | Biological Psychology | Developmental Neuroscience

Abstract

Aims: This study investigates the nuanced effect of the CACNA1C mutation on neurocognition and neurodevelopment via an extended study of the Timothy Syndrome (TS) mediated Autism Spectrum Disorder (ASD) mouse model – TS2-neo. It includes: (1) an expanded assessment of the TS2-neo behavioral phenotype, and (2) a comprehensive histological analysis of cortical structural and laminar features.

Methods: 24 age-matched male mice – 12 TS2-neo (B6.Cg-Cacna1ctm2Itl, knock-in G406R mutation), 12 WT (C57BL/6J) – were tested on paradigms examining motor, socio-communicative and cognitive abilities. Neural tissue was processed for either volumetric analysis through Nissl stain (8 TS2-neo, 8 WT) or immunohistochemical analysis (4 TS2-neo, 4 WT). Statistics for all analyses were run through SPSS 19.

Results: Analyses of task performance illustrate that TS2-neo mice show impaired sensorimotor and procedural motor learning ability, socio-communicative deficits, increased habitual digging, and strengths in detecting temporal auditory sound cues as compared to WT controls (p<.05). Histological analyses of TS2-neo brains reveal significant and marginal decreases in the volumes of the external capsule and fornix (p<.05; p=.059), aberrant patterns of cortical lamination (p<.05), and atypical expression of cortical neuron subpopulations marked by Satb2 and Foxp2 (p<.1).

Discussion: In this paper we replicate and extend the “ASD-like” behavioral phenotype of the TS2-neo mouse model and report novel findings of atypical white matter development and cortical laminar anomalies in the relative thickness of input and output layers and distribution of markers for projecting neuron populations. These results shed light on possible shifts in global cortico-cortical and cortico-sub-cortical connections in TS-mediated ASD.

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