Dendritic spines are the sites of most excitatory synapses in the brain. Changes in spine density and morphology are of significance for the formation of learning and memory, and spine dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that likely directly contributes to cognitive dysfunctions. The Rho GEF kalirin has been shown to control dendritic spine morphogenesis via its activation of the small GTPase Rac. Rac in turn activates the p21-activated kinase, Pak, which in turn mediates actin cytoskeletal rearrangement and consequent changes in spine morphology. The recent development of the first kalirin KO mouse will be used to determine if the previously characterized kalirin- Rac and kalirin-GluR1 in vitro interactions are dysregulated in kalirin KO animals in vivo. Furthermore we will characterize the cognitive deficits of kalirin KO animals and determine the synaptic signaling deficits that mediate these deficits. Last, we will examine how kalirin loss affects synaptic structure and function in vivo. Because Alzheimer's disease (AD) is characterized by cognitive and dendritic spine deficits that closely parallel those induced by kalirin down-regulation, and because kalirin loss is a common feature of human Alzheimer's patients, understanding the role of kalirin in vivo is of extreme therapeutic relevance. Overall, the proposed aims will have enormous implications for understanding how dendritic spine dysfunctions affect learning a memory in vivo, an area of neuroscience is much is speculated, but little is known. In addition, because kalirin loss is evident in the forebrain of Alzheimer's patients, and because we present preliminary evidence indicating that kalirin loss is characteristic of a cellular Alzheimer's model, the characterization of the kalirin KO mouse may in conjunction with addition studies identify kalirin as a therapeutic target as has been suggested for the kalirin effector molecules Pak and GluR1. Lay Summary: Dendritic spines are sites of most excitatory synapses in the brain. By understanding how signaling molecules within dendritic spines affect spine density/morphology and how these molecules affect cognitive functions such as learning and memory, a better understanding how spine aberrations affect cognition will be determined. In addition, an understanding of the effects of synaptic dysfunction on cognition is of fundamental importance to more completely understanding the pathology of Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AG031621-02
Application #
7845018
Study Section
Special Emphasis Panel (ZRG1-F03A-F (20))
Program Officer
Refolo, Lorenzo
Project Start
2009-05-01
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$28,301
Indirect Cost
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Cahill, Michael E; Remmers, Christine; Jones, Kelly A et al. (2013) Neuregulin1 signaling promotes dendritic spine growth through kalirin. J Neurochem 126:625-35
Deo, Anthony J; Cahill, Michael E; Li, Siyu et al. (2012) Increased expression of Kalirin-9 in the auditory cortex of schizophrenia subjects: its role in dendritic pathology. Neurobiol Dis 45:796-803
Cahill, M E; Jones, K A; Rafalovich, I et al. (2012) Control of interneuron dendritic growth through NRG1/erbB4-mediated kalirin-7 disinhibition. Mol Psychiatry 17:1, 99-107
Nicholson, Daniel A; Cahill, Michael E; Tulisiak, Christopher T et al. (2012) Spatially restricted actin-regulatory signaling contributes to synapse morphology. J Neurochem 121:852-60
Srivastava, Deepak P; Copits, Bryan A; Xie, Zhong et al. (2012) Afadin is required for maintenance of dendritic structure and excitatory tone. J Biol Chem 287:35964-74
Penzes, Peter; Cahill, Michael E (2012) Deconstructing signal transduction pathways that regulate the actin cytoskeleton in dendritic spines. Cytoskeleton (Hoboken) 69:426-41
Xie, Zhong; Cahill, Michael E; Radulovic, Jelena et al. (2011) Hippocampal phenotypes in kalirin-deficient mice. Mol Cell Neurosci 46:45-54
Penzes, Peter; Cahill, Michael E; Jones, Kelly A et al. (2011) Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 14:285-93
Xie, Zhong; Cahill, Michael E; Penzes, Peter (2010) Kalirin loss results in cortical morphological alterations. Mol Cell Neurosci 43:81-9
Cahill, Michael E; Xie, Zhong; Day, Michelle et al. (2009) Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes. Proc Natl Acad Sci U S A 106:13058-63