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THE CONTRIBUTION OF SOMATOSTATIN-EXPRESSING (SOM+) INTERNEURONS TO THE PTEN MODEL OF AUTISM SPECTRUM DISORDER

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Date Issued:
2021
Abstract/Description:
Autism spectrum disorder (ASD) is a complex disorder with large individual variability, where every case has differences in the type and severity of symptoms. Despite the recent increase in diagnoses, scientists have advanced considerably less in their understanding of the mechanisms of ASD because few individual genes that are implicated in ASD are mutated in much more than 1% of patients. One proposed mechanism is that the dysfunction of GABAergic interneurons may play a role in the development and progression of the disorder by interrupting the excitatory and inhibitory balance of neural networks. In our research, we elucidate the role of one class of interneurons in ASD by knocking out a high-risk gene (phosphatase and tensin homologue on chromosome ten, or PTEN) selectively in somatostatinexpressing (SOM+) interneurons. Since many symptoms of autism spectrum disorder present themselves as social anxieties, we test our mouse model in a variety of settings to observe social interaction and social preference, anxiety-like behavior, and repetitive stereotyped behavior. We found that in the SOM+ conditional knockout of PTEN, mice had elevated levels of anxiety and fear recall, suggesting a potential disruption of amygdala function. We then investigated potential dysfunction at the cellular and circuit levels using confocal microscopy, electrophysiology, and 2P local circuit mapping. We found that SOM+ cells lacking PTEN were overgrown morphologically, with larger cell bodies and larger, more complex dendritic arbors. Additionally, SOM+ cells in the central amygdala (CeA) lacking PTEN had elevated levels of excitatory drive from the basolateral amygdala (BLA) as well as a drastic disruption of lateral inhibition within the CeA, seen by decreased connection probability and reduced inhibitory post synaptic currents. Given what is known about central amygdala circuitry, these deficits in CeA SOM+ neuron activity conceivably underlie the fear and anxiety-related phenotype observed in mice with a conditional SOM+ PTEN knockout.
Title: THE CONTRIBUTION OF SOMATOSTATIN-EXPRESSING (SOM+) INTERNEURONS TO THE PTEN MODEL OF AUTISM SPECTRUM DISORDER.
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Name(s): Holford, Timothy W. , author
Bolton, M. McLean , Thesis advisor
Florida Atlantic University, Degree grantor
Department of Biological Sciences
Charles E. Schmidt College of Science
Type of Resource: text
Genre: Electronic Thesis Or Dissertation
Date Created: 2021
Date Issued: 2021
Publisher: Florida Atlantic University
Place of Publication: Boca Raton, Fla.
Physical Form: application/pdf
Extent: 204 p.
Language(s): English
Abstract/Description: Autism spectrum disorder (ASD) is a complex disorder with large individual variability, where every case has differences in the type and severity of symptoms. Despite the recent increase in diagnoses, scientists have advanced considerably less in their understanding of the mechanisms of ASD because few individual genes that are implicated in ASD are mutated in much more than 1% of patients. One proposed mechanism is that the dysfunction of GABAergic interneurons may play a role in the development and progression of the disorder by interrupting the excitatory and inhibitory balance of neural networks. In our research, we elucidate the role of one class of interneurons in ASD by knocking out a high-risk gene (phosphatase and tensin homologue on chromosome ten, or PTEN) selectively in somatostatinexpressing (SOM+) interneurons. Since many symptoms of autism spectrum disorder present themselves as social anxieties, we test our mouse model in a variety of settings to observe social interaction and social preference, anxiety-like behavior, and repetitive stereotyped behavior. We found that in the SOM+ conditional knockout of PTEN, mice had elevated levels of anxiety and fear recall, suggesting a potential disruption of amygdala function. We then investigated potential dysfunction at the cellular and circuit levels using confocal microscopy, electrophysiology, and 2P local circuit mapping. We found that SOM+ cells lacking PTEN were overgrown morphologically, with larger cell bodies and larger, more complex dendritic arbors. Additionally, SOM+ cells in the central amygdala (CeA) lacking PTEN had elevated levels of excitatory drive from the basolateral amygdala (BLA) as well as a drastic disruption of lateral inhibition within the CeA, seen by decreased connection probability and reduced inhibitory post synaptic currents. Given what is known about central amygdala circuitry, these deficits in CeA SOM+ neuron activity conceivably underlie the fear and anxiety-related phenotype observed in mice with a conditional SOM+ PTEN knockout.
Identifier: FA00013775 (IID)
Degree granted: Dissertation (Ph.D.)--Florida Atlantic University, 2021.
Collection: FAU Electronic Theses and Dissertations Collection
Note(s): Includes bibliography.
Subject(s): Autism Spectrum Disorder
Somatostatin
Interneurons
Amygdala
Persistent Link to This Record: http://purl.flvc.org/fau/fd/FA00013775
Use and Reproduction: Copyright © is held by the author with permission granted to Florida Atlantic University to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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Host Institution: FAU
Is Part of Series: Florida Atlantic University Digital Library Collections.