Dissertation/Thesis Abstract

Studies on the Regulation of Long-term Synapse Stability, Dendrite Maintenance, and Animal Behavior: (1) Laminin-integrin Alpha3 Signaling and (2) Disruption in Alzheimer's Disease Model Mice
by Kerrisk, Meghan Elizabeth, Ph.D., Yale University, 2014, 215; 3580725
Abstract (Summary)

Most dendrite branches and many dendritic spines are stable for long periods of time (Holtmaat et al., 2005, Trachtenberg et al., 2002, Yang et al., 2009). Destabilization of these structures compromises brain function and is a major contributing factor to psychiatric and neurodegenerative diseases, such as Alzheimer's disease (AD) (Kulkarni and Firestein, 2012). Research over the past decade has elucidated distinct signaling cascades that control long-term dendrite and dendritic spine stability, most of which impinge on regulatory pathways of the neuronal cytoskeleton (Koleske, 2013, Lin and Koleske, 2010). In my research, I identified a laminin-integrin α3 signaling pathways that plays a key role in regulating neuronal stability. In my first aim, I find, dendrites, dendritic spines, and synapses develop normally in mice with selective loss of integrin α3 in excitatory forebrain neurons, reaching their mature sizes and densities through P21. However, by P42 integrin α3 mutant mice exhibit significant reductions in hippocampal dendrite arbor size and complexity, loss of dendritic spine and synapse densities, and impairments in hippocampus-dependent behavior. Additionally, I find that integrin α3 signals to the Arg nonreceptor tyrosine kinase and activates p190RhoGAP, which inhibits RhoA GTPase and regulates hippocampal dendrite and synapse stability and mouse behavior (Kerrisk et al., 2013).

In my second research aim, I sought to determine the extracellular ligand that activates integrin α3 in vivo to regulate long-term synapse and dendrite stability. Laminins are a class of heterotrimeric extracellular proteins that are well known ligands for integrin receptors and have an important role in synapse structure and function (Belkin and Stepp, 2000, Egles et al., 2007). My preliminary results suggest that the specific laminin chains α5 and β2 play an essential role in long-term dendrite maintenance, dendritic spine stability, and animal behavior. In the hippocampus, laminin expression turns on at P15 and increases into adulthood. Loss of laminin α5 from excitatory neurons results in an age-dependent loss of dendrite length and branchpoints. However, laminin α5 knockout mice have increased hippocampal dendritic spine densities and impaired behavior in novel object recognition. Furthermore, I find laminins α5 and β2 interact genetically with integrin α3 to regulate long-term dendrite maintenance, dendritic spine density, and animal behavior. Taken together these results implicate laminin α5 and β2 signaling to integrin α3β1 to control neuronal stability and function.

The loss of dendrite arbor and dendritic spine stability in humans is a major contributing factor to the pathology of neurodegenerative diseases (Kulkarni and Firestein, 2012, Lin and Koleske, 2010). In particular, AD is a progressive neurodegenerative dementia characterized by amyloid plaque accumulation, synapse and dendrite loss, and cognitive impairment. Transgenic mouse models of AD recapitulate several aspects of this disease and provide a useful model system for studying elements of AD progression (Price et al., 1998). Inbred AD mouse strains have been previously shown to exhibit behavioral deficits and amyloid plaque deposition by 9 months of age. In my third research aim, I show the onset of memory-based behavioral impairments is delayed in outcrossed AD mice relative to inbred mice on a C57BL/6 background. Within the forebrain, I find that inbred AD mice have significantly higher amyloid plaque burden at 12 months than outcrossed AD mice of the same age. Analysis of soluble Aβ revealed that elevated expression levels of this protein correlate with the degree of behavioral impairment in both strains. Taken together, these findings suggest that animal behavior, amyloid plaque deposition, and processing are sensitive to genetic differences between mouse strains (Couch et al., 2013).

Indexing (document details)
Advisor: Koleske, Anthony J.
Commitee:
School: Yale University
School Location: United States -- Connecticut
Source: DAI-B 75/09(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Neurosciences, Biochemistry
Keywords: Alzheimer's, Dendrite, Integrin, Laminin, Maintenance, Synapse
Publication Number: 3580725
ISBN: 9781321051209
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