Failure of learning and memory is one of the most debilitating aspects of aging and neurodegenerative disease, yet we do not understand the basic mechanisms of these crucial brain processes and we cannot intervene effectively in these deficits. Learning and memory takes place primarily at synapses. Presynaptic calcium (Cav2.1) channels initiate neurotransmitter release at most synapses in the brain. The activity of these channels is tightly regulated by a large complex of signaling proteins, including calmodulin and related calcium sensor proteins. The classic work of Katz and Miledi in the 1960's first described short-term synaptic facilitation and depression. These forms of short-term synaptic plasticity shape the postsynaptic response to trains of action potentials impinging on the presynaptic terminal and thereby encode information contained in the frequency and pattern of action potentials for transmission to the postsynaptic cell. The mechanisms that underlie short-term synaptic plasticity on the presynaptic side of the synapse remain poorly understood. Our recent work has implicated Ca channel regulation as an important component of short-term synaptic plasticity. Studies of Cav2.1 channels transfected in individual superior cervical ganglion neurons in cell culture showed that both short-term synaptic facilitation and the rapid phase of synaptic depression are blocked by mutations that prevent facilitation and inactivation of Cav2.1 channel activity by calcium/calmodulin and other calcium sensor proteins. Based on these results, we hypothesize that regulation of Cav2.1 channels by calmodulin and calcium sensor proteins is an important contributor to short-term synaptic plasticity at synapses in the hippocampus and that this form of synaptic plasticity is important for spatial learning and memory. We will address this hypothesis at the molecular level by developing a high-resolution molecular model for the interacting domains of Cav2.1 channels and CaS proteins based on Rosetta structural modeling, chemical crosslinking, and high-resolution mass spectrometry. We will address this hypothesis at the functional and behavioral levels using a recently developed knock-in mouse line in which the IQ-like motif that is required for CaM-dependent facilitation of Cav2.1 channels has been mutated to prevent facilitation of channel activity (Cav2.1/IM-AA mice). We will determine the role of regulation of Cav2.1 channels in short-term synaptic plasticity of neural circuits in hippocampal slices from wild-type and IM-AA mutant mice, which are deficient in presynaptic plasticity in the nerve terminals of CA3 neurons. We will explore the role of regulation of Cav2.1 channels and short-term synaptic plasticity in spatial learning and memory in wild-type and IM-AA mutant mice, which are deficient in context-dependent fear conditioning. Our experiments with this unique mouse model will give new insights into the mechanism of short-term presynaptic plasticity in hippocampal neurons and its role in spatial learning and memory. This information will be essential to understanding of failure of spatial learning and memory in aging and disease.

Public Health Relevance

Learning and memory depend on modification of the strength of communication between nerve cells at synapses, a process called synaptic plasticity. In this work we will analyze the molecular and cellular mechanism of short-term synaptic plasticity, which takes place on the millisecond time scale and is important for encoding and transmitting information in neurons. Our results will help to understand learning and memory in the normal brain and pave the way for future understanding of the failure of these processes in aging and neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS022625-27A1
Application #
8576705
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Stewart, Randall R
Project Start
1985-09-09
Project End
2017-06-30
Budget Start
2013-09-15
Budget End
2014-06-30
Support Year
27
Fiscal Year
2013
Total Cost
$337,969
Indirect Cost
$119,219
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yan, Jin; Leal, Karina; Magupalli, Venkat G et al. (2014) Modulation of CaV2.1 channels by neuronal calcium sensor-1 induces short-term synaptic facilitation. Mol Cell Neurosci 63:124-31
Catterall, William A; Leal, Karina; Nanou, Evanthia (2013) Calcium channels and short-term synaptic plasticity. J Biol Chem 288:10742-9
Magupalli, Venkat G; Mochida, Sumiko; Yan, Jin et al. (2013) Ca2+-independent activation of Ca2+/calmodulin-dependent protein kinase II bound to the C-terminal domain of CaV2.1 calcium channels. J Biol Chem 288:4637-48
Few, Alexandra P; Nanou, Evanthia; Watari, Hirofumi et al. (2012) Asynchronous Ca2+ current conducted by voltage-gated Ca2+ (CaV)-2.1 and CaV2.2 channels and its implications for asynchronous neurotransmitter release. Proc Natl Acad Sci U S A 109:E452-60
Nanou, Evanthia; Martinez, Gilbert Q; Scheuer, Todd et al. (2012) Molecular determinants of modulation of CaV2.1 channels by visinin-like protein 2. J Biol Chem 287:504-13
Marshall, Misty R; Clark 3rd, John Patrick; Westenbroek, Ruth et al. (2011) Functional roles of a C-terminal signaling complex of CaV1 channels and A-kinase anchoring protein 15 in brain neurons. J Biol Chem 286:12627-39
Few, Alexandra P; Nanou, Evanthia; Scheuer, Todd et al. (2011) Molecular determinants of CaV2.1 channel regulation by calcium-binding protein-1. J Biol Chem 286:41917-23
Mochida, Sumiko; Few, Alexandra P; Scheuer, Todd et al. (2008) Regulation of presynaptic Ca(V)2.1 channels by Ca2+ sensor proteins mediates short-term synaptic plasticity. Neuron 57:210-6
Jiang, Xin; Lautermilch, Nathan J; Watari, Hirofumi et al. (2008) Modulation of CaV2.1 channels by Ca2+/calmodulin-dependent protein kinase II bound to the C-terminal domain. Proc Natl Acad Sci U S A 105:341-6
Keith, Ryan K; Poage, Robert E; Yokoyama, Charles T et al. (2007) Bidirectional modulation of transmitter release by calcium channel/syntaxin interactions in vivo. J Neurosci 27:265-9

Showing the most recent 10 out of 64 publications