Date of Completion
2024
Thesis Type
College of Arts and Science Honors
Department
Neurological Sciences
First Advisor
Jeremy Barry
Second Advisor
Jom Hammack
Third Advisor
Paul Besaw
Keywords
ASD, PTEN, Electrophysiology, Hippocampus, Spatial Learning, Autism
Abstract
ASD is a prevalent neuropsychiatric disorder without a solid understanding of the relationship between genetic influence to morphology and behavior. One gene mutation associated with some cases is PTEN. When mutated in neurons, overgrowth and hyperexcitability occur. In the animal model of PTEN Ko in the dentate gyrus, this can lead to spatial deficits, specifically by altering the biophysics of granule cells. It is hypothesized social and spatial deficits in ASD are caused by alterations to cell growth and resulting shifts in biophysics which can lead to disorganized hippocampal circuit function. In this study, we knock out PTEN out while also implanting DREADDs in a fraction of dentate gyrus granule cells in mice. We then test spatial accuracy and cognition through behavior, and hippocampal circuit function through electrophysiological recording. This is carried out before and after activating DREADDs, selectively silencing PTEN Ko neurons. We hypothesize that PTEN Ko mice will show deficits on spatial tasks, and that silencing Ko cells should attenuate cognitive deficits and normalize electrophysiological measures resulting from hyperexcitable PTEN Ko cells. Here, we show that PTEN Ko mice demonstrate learning and memory deficits learning a spatial accuracy task. DREADDs activation increased task performance during some rotated trials with hidden cues for PTEN Ko but not Control mice. Electrophysiological analysis revealed that compared to controls, theta and gamma amplitude were reduced in PTEN ko mice. In line with our hypothesis and changes to granule cell physiology, we found significant increases to the density of inputs localized to the second molecular layer of dentate gyrus. In a subset of animals (3/8), the increased theta scale input density coincided with focal zones for the generation of IEDs, enough that CSD analysis of the bottom blade could predict the presence of IEDs. DREADDs activation decreased IED rate by half or more in these animals and reduced the density of inputs in the second blade of DG. IHC data indicates that 3-4 Ko mice had Ko granule cells migrate outside of the cell layer, forming heterotopias, and that the presence of heterotopias was highly correlated with IEDs. This finding suggests structural abnormalities are a feature of this model and may be a significant source of hyperstability, increasing clinical translational relevance to the PTEN Ko model.
Recommended Citation
Elste, Noah H., "Reversing Cognitive Deficits in the PTEN KO Model of ASD: From Behavior to In-Vivo Electrophysiological Recording" (2024). UVM College of Arts and Sciences College Honors Theses. 132.
https://scholarworks.uvm.edu/castheses/132