The objective of this proposal is to characterize the mechanisms mediated by the protein kalirin that control synaptic structural and functional plasticity in pyramidal neurons. Building upon data produced in the previous grant period, and using a novel mouse model we have recently generated, we will examine the role of an important molecular regulator of dendritic spine plasticity. As both spine density and kalirin expression are reduced in schizophrenic patients'brains, these studies are expected to provide important insight into the mechanisms of spine pathology in mental disorders. Modifications in spiny excitatory synapse structure and function modulate synaptic transmission and plasticity, and underlie cognitive functions. Conversely, altered spine plasticity contributes to the pathogenesis of several mental disorders. Hence, understanding the molecular mechanisms that control spiny synapse plasticity and pathology will provide essential insight into the neurobiology of cognitive functions and mental disorders that affect cognition. Synapse structure and function are controlled by a complex network of interactions between numerous proteins. Our previous studies have established the postsynaptic protein kalirin as an important regulator of synaptic structural plasticity. Importantly, kalirin has recently been implicated in several mental disorders including schizophrenia. Kalirin is a brain-specific guanine-nucleotide exchange factor which activates the small GTPase Rac1 and its most abundant form, kalirin-7, is highly enriched in spines. In the previous funding period we demonstrated that kalirin-7 plays an important role in activity-dependent synaptic structural and functional plasticity downstream of NMDA receptors and CaMKII. We have shown that kalirin also regulates AMPA receptors in spines, and mediates N-cadherin-dependent synaptic adhesion signaling. We have also generated a full knockout of the KALRN gene (KALRN-/-) in mice, and found that this results in a robust and cortex-specific reduction in Rac1 activation and in the number of functional spiny excitatory synapses. KALRN-/- mice have impairments in specific cognitive functions. In this proposal we will dissect the functional roles of kalirin signaling in spiny synapse morphogenesis and plasticity. We hypothesize that kalirin signaling plays crucial and specific roles in synapse function and spine stability/dynamics. We propose the following Specific Aims: 1) To characterize the mechanisms underlying kalirin-dependent regulation of AMPA receptor-mediated transmission and plasticity. 2) To chart the time course and characterize the mechanisms of kalirin-dependent spine stability and dynamics. 3) To characterize the role of kalirin signaling in N-cadherin-dependent spine morphogenesis in vivo. 1

Public Health Relevance

The objective of this proposal is to characterize the mechanisms mediated by the protein kalirin that control synaptic structural and functional plasticity in pyramidal neurons. Building upon data produced in the previous grant period, and using a novel mouse model we have recently generated, we will examine the role of an important molecular regulator of dendritic spine plasticity. As both spine density and kalirin expression are reduced in schizophrenic patients'brains, these studies are expected to provide important insight into the mechanisms of spine pathology in mental disorders. 1

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH071316-09
Application #
8437271
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Asanuma, Chiiko
Project Start
2004-07-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
9
Fiscal Year
2013
Total Cost
$360,313
Indirect Cost
$122,713
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Moyer, Caitlin E; Erickson, Susan L; Fish, Kenneth N et al. (2016) Developmental Trajectories of Auditory Cortex Synaptic Structures and Gap-Prepulse Inhibition of Acoustic Startle Between Early Adolescence and Young Adulthood in Mice. Cereb Cortex 26:2115-26
Liu, Xiaojie; Chen, Yao; Tong, Jiaqing et al. (2016) Epac Signaling Is Required for Cocaine-Induced Change in AMPA Receptor Subunit Composition in the Ventral Tegmental Area. J Neurosci 36:4802-15
Blizinsky, Katherine D; Diaz-Castro, Blanca; Forrest, Marc P et al. (2016) Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub. Proc Natl Acad Sci U S A 113:8520-5
Grubisha, Melanie J; Lin, Chien-Wei; Tseng, George C et al. (2016) Age-dependent increase in Kalirin-9 and Kalirin-12 transcripts in human orbitofrontal cortex. Eur J Neurosci 44:2483-2492
Shelton, Micah A; Newman, Jason T; Gu, Hong et al. (2015) Loss of Microtubule-Associated Protein 2 Immunoreactivity Linked to Dendritic Spine Loss in Schizophrenia. Biol Psychiatry 78:374-85
Gao, R; Penzes, P (2015) Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. Curr Mol Med 15:146-67
MacDonald, Matthew L; Ding, Ying; Newman, Jason et al. (2015) Altered glutamate protein co-expression network topology linked to spine loss in the auditory cortex of schizophrenia. Biol Psychiatry 77:959-68
Jones, Kelly A; Eng, Andrew G; Raval, Pooja et al. (2014) Scaffold protein X11α interacts with kalirin-7 in dendrites and recruits it to Golgi outposts. J Biol Chem 289:35517-29
Russell, Theron A; Blizinsky, Katherine D; Cobia, Derin J et al. (2014) A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness. Nat Commun 5:4858
Remmers, Christine; Sweet, Robert A; Penzes, Peter (2014) Abnormal kalirin signaling in neuropsychiatric disorders. Brain Res Bull 103:29-38

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