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)
Type
Research Project (R01)
Project #
5R01MH071316-10
Application #
8606893
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Asanuma, Chiiko
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60611
Smith, Katharine R; Kopeikina, Katherine J; Fawcett-Patel, Jessica M et al. (2014) Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapses. Neuron 84:399-415
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
VanLeeuwen, Jon-Eric; Rafalovich, Igor; Sellers, Katherine et al. (2014) Coordinated nuclear and synaptic shuttling of afadin promotes spine plasticity and histone modifications. J Biol Chem 289:10831-42
Remmers, Christine; Sweet, Robert A; Penzes, Peter (2014) Abnormal kalirin signaling in neuropsychiatric disorders. Brain Res Bull 103:29-38
Srivastava, Deepak P; Woolfrey, Kevin M; Penzes, Peter (2013) Insights into rapid modulation of neuroplasticity by brain estrogens. Pharmacol Rev 65:1318-50
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; Goldszer, Isaac M; Li, Siyu et al. (2013) PAK1 protein expression in the auditory cortex of schizophrenia subjects. PLoS One 8:e59458
Penzes, Peter; Buonanno, Andres; Passafaro, Maria et al. (2013) Developmental vulnerability of synapses and circuits associated with neuropsychiatric disorders. J Neurochem 126:165-82
Penzes, Peter; Remmers, Christine (2012) Kalirin signaling: implications for synaptic pathology. Mol Neurobiol 45:109-18
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

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