A Cerebellar Role in the Development and Regulation of Autism-Relevant Behavior in Neurodevelopmental Disorders

Cerebellar dysfunction is a consistent observation in autism spectrum disorders (ASD) and associated genetic disorders like Fragile X Syndrome (FXS). Growing evidence for cerebellar regulation of behaviors that characterize these disorders has provided a greater understanding of non-motor roles for the cerebellum. Consistent observations of cerebellar pathology in human and mouse models of FXS indicate a potential contribution of cerebellar activity to ASD-relevant behavior impairments that has yet to be fully described. Here, we define a role for cerebellar Fmr1 in ASD-relevant behaviors a model of cerebellar dysfunction and show normal social and sensory behaviors require cerebellar expression of Fmr1. We show that cerebellar Fmr1 is sufficient to rescue those deficits observed a model of translationally relevant global Fmr1 loss. We also demonstrate a modulatory role for cerebellar domain RCrus1 in the presentation of social behaviors in these Fmr1 models. To further our understanding genetic mechanisms in ASD and how to leverage them in the development of therapeutics, we investigated critical periods of developmental vulnerability in another genetic model of ASD, tuberous sclerosis complex (TSC). Specifically addressing how the timing abnormal cerebellar development contributes to the onset of ASD-relevant behaviors. Through timed pharmacologic manipulation of the mTOR pathway, which is overactive in models of TSC, we identified independent critical periods for the development of cerebellar-mediated social and restrictive and repetitive behaviors. Together these studies highlight the translational impact for cerebellar modulation of ASD-relevant behaviors in multiple genetic models of ASD, in an effort to direct future study of the cerebellum as a therapeutic target.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Neuroscience

Grantor

UT Southwestern Medical Center

Year dc:date.issued

2022

Author dc:creator

• Gibson, Jennifer

Advisor dc:contributor.advisor

• Lai, Helen

Committee members dc:contributor.committeemember

• Tsai, Peter
• Huber, Kimberly M.
• Konopka, Genevieve

• Cerebellum
• Cognition Disorders
• Fragile X Syndrome
• Social Behavior
• Autism Spectrum Disorder

Language dc:language.iso

en

Identifier

1482732345

OAI record oai:identifier

https://utswmed-ir.tdl.org/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Autswmed-ir.tdl.org%3A2152.5%2F10461