Dissertation
Molecular mechanisms of neurodevelopmental disorders revealed by 16p11.2 hemideletion
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008467
Abstract
Neurodevelopmental disorders (NDDs) are a broad spectrum of conditions that emerge early in development and result in pervasive impairments in functioning that present barriers for individuals affected and their support systems. The underlying molecular mechanisms that mediate these challenges are not well understood and are complicated by an array of genetic and environmental contributors. Thus, there are a lack of therapeutic approaches available to support the most difficult challenges associated with NDDs. This dissertation aims to address this knowledge gap by elucidating the molecular impact of 16p11.2 hemideletion on the striatum. 16p11.2 hemideletion (16p del), a copy number variation resulting from loss of 27 genes on the short arm of chromosome 16, is associated with a high penetrance of NDDs. The striatum is a sub-cortical brain region hypothesized to be a common node impacted in NDDs including autism spectrum disorder (ASD). Because 16p del is one of the most common risk factors for NDDs including ASD, the insights gleaned from its effect on a key NDD-associated brain region promises to pave the way for better support both for individuals with 16p del and NDDs more broadly (Chapter 1).
Chapter 2 arises from investigation of striatal gene expression and implicates innate immune activation in the striatum of 16p del mice. Members of the complement system are upregulated selectively in the 16p del striatum, and this upregulation converges on the potentiation of signaling through anaphylatoxin receptor C3aR. Pharmacological inhibition of C3aR reduces hyperactive behavior in 16p del mice. Transcriptional signatures in the 16p del striatum are indicative of reactive microglia, and morphological analyses of microglia suggest an activation profile in the striatum that differs from that in the cortex. However, reducing inflammation does not reduce locomotor behavior specifically in 16p mice, and C3aR inhibition does not ameliorate the transcriptional signatures of microglial activation, suggesting that canonical pro-inflammatory microglial activation is not responsible for hyperactive behavior in 16p del mice. Instead, C3aR inhibition lessens the activation of interferon responsive genes in 16p del mice, implicating complement-interferon crosstalk in the striatum as a promising mechanism underlying NDD-relevant behavior due to 16p del. These studies suggest that innate immune activation within the striatum contributes to the behavioral impacts of 16p del.
In Chapter 3, the mechanisms underpinning male-specific reward learning deficits in 16p del mice were investigated. 16p del mice exhibit multiple NDD-relevant behaviors specifically in male animals, mirroring the striking sex bias in the prevalence and presentation of NDDs including ASD in humans. Striatal D1-expressing medium spiny neurons (D1 MSNs), a major striatal output population responsible for responding to reward, play a crucial role in mediating male-specific operant learning deficits as conditional deletion of the 16p del syntenic region in D1 MSNs reproduces this cognitive impairment specifically in male animals. Investigations of gene expression and histone post-translational modifications in D1 MSNs converge on the sexspecific regulation of chromatin and DNA repair in 16p del. yH2AX, a histone variant marking DNA double-strand breaks, is increased specifically in the D1 MSNs of 16p del males. Crucially, overexpressing Ino80e, a member of the Ino80 chromatin remodeling complex within the 16p del region, ameliorates this elevation in DNA damage. These data suggest that the sex-specific regulation of chromatin underlies DNA damage in male 16p del D1 MSNs and implicates disruption of DNA repair as a mechanism underlying striatal-related neurobehavioral deficits including reward learning impairments in the context of NDDs.
Together, these studies of 16p del mice point to disruption of the epigenetic mechanisms of DNA repair and downstream innate immune activation as key molecular mechanisms underlying NDD-relevant behaviors. These mechanisms may represent a common underlying mechanism impacted by a range of genetic contributors to NDDs and may also provide insight into the emerging link between ASD and neurodegenerative conditions (Chapter 4). This work lays a foundation for future investigations both to mechanistically define DNA repair dysfunction and innate immune activation in NDDs and develop therapeutic strategies to provide lifelong support for the most challenging barriers faced by individuals with NDDs (Chapter 5).
Details
- Title: Subtitle
- Molecular mechanisms of neurodevelopmental disorders revealed by 16p11.2 hemideletion
- Creators
- Benjamin A. Kelvington
- Contributors
- Ted Abel (Advisor)Adele Stewart (Committee Member)Snehajyoti Chatterjee (Committee Member)Sarah Ferri (Committee Member)Hanna Stevens (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Pharmacology)
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008467
- Publisher
- University of Iowa
- Number of pages
- xxi, 176 pages
- Copyright
- Copyright 2026 Benjamin A. Kelvington
- Language
- English
- Date submitted
- 04/10/2026
- Description illustrations
- Illustrations, graphs, charts, tables
- Description bibliographic
- Includes bibliographical references (pages 138-176).
- Public Abstract (ETD)
Individuals who have neurodevelopmental disorders (NDDs) and their support systems experience barriers that impact functioning in daily life. Limited knowledge of the biological processes that create barriers prevents the development of better support. Here, I assess the impact of one of the most common genetic conditions associated with NDDs, 16p11.2 hemideletion (16p del), on the brain and behavior. I find that 16p del impacts a brain region that controls many behaviors closely linked to NDD symptoms called the striatum. In one chapter I learn that 16p del activates the innate immune system in the striatum. Blocking this activation by preventing signaling from the complement system, which is a part of the immune system that also functions in the brain, reduces hyperactive behavior in 16p del mice. This indicates that immune responses in the striatum worsen hyperactive behavior in the context of NDDs. In another chapter, I learn that specific neurons within the striatum, D1-expressing medium spiny neurons, are responsible for male animals with 16p del being less able to learn action-reward associations. In addition to their role in behavior, these neurons build up excess DNA damage. This result provides a clue as to how maintaining the integrity of the genome is a key function of genes associated with NDDs. Together, these studies suggest that disruption of DNA repair and activation of the immune system may be common processes occurring in NDDs, and these processes may be more pronounced in the striatum. This work sets the stage for more detailed investigations and paves a path for the development of therapeutic supports to address the barriers presented by NDDs.
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9985177376802771
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