Failure of learning and memory is one of the most debilitating aspects of aging and neurodegenerative disease, yet we do not understand the basic underlying mechanisms and we cannot intervene effectively. Learning and memory takes place primarily at synapses. Calcium (Ca) entry through presynaptic voltage-gated Ca channels (Cav2.1) initiates neurotransmitter release at most synapses in the brain. Cav2.1 activity is tightly regulated by a complex of signaling proteins, including calmodulin (CaM), CaM-related Ca sensor (CaS) proteins, SNARE proteins, and synaptotagmins (Syts). Classic work first described short-term synaptic facilitation and depression, which shape the postsynaptic response to trains of action potentials and thereby encode information contained in the frequency and pattern of action potentials for transmission to the postsynaptic cell. Mechanisms that underlie short-term presynaptic plasticity remain poorly understood. Our recent work implicates Cav2.1 regulation in short-term synaptic plasticity and in spatial learning and memory. Studies of Cav2.1 channels expressed in presynaptic 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 by Ca/CaM and other CaS proteins. Other recent studies implicate the Ca-sensing protein Syt-7 in short-term synaptic plasticity. We hypothesize that regulation of Cav2.1 channels by CaM and related CaS proteins plus Ca-sensing by Syt-7 work together to mediate and regulate short-term synaptic plasticity in the hippocampus and that this novel form of synaptic plasticity is important for neural circuit function and for spatial learning and memory. We will address this new hypothesis through molecular and structural studies of Cav2.1 regulation and through physiological studies of mutant mice. We will use crosslinking/mass spectrometry and X-ray crystallography of a new Cav2.1/CaM complex to define the structural basis for Cav2.1 regulation by CaM and related CaS proteins. Our mutant mouse line in which the IQ-like motif required for Ca/CaM-dependent facilitation of Cav2.1 has been mutated (IM-AA) and mice in which the gene for Syt-7 has been disrupted (Syt-7/KO) both have impaired short-term synaptic plasticity. We will determine the relative roles of Ca-dependent regulation of Cav2.1 channels and Ca sensing by Syt-7 in plasticity of excitatory and inhibitory hippocampal synapses in these mutant mice. We will examine changes in long-term potentiation of hippocampal synapses, which is deficient in IM-AA mice. We will explore the functional roles of Cav2.1 regulation and Ca sensing in spatial learning and memory, which are deficient in IM-AA mice, and we will also study these neural processes in Syt-7 mice and double-mutant IM-AA/Syt-7 mice. We will elucidate the effects of altered synaptic plasticity on neural circuit functions, including theta waves, sharp-wave ripples, and place cell formation and extinction, and we will connect these changes in neural circuit function with deficits in spatial learning and memory in IM-AA and Syt-7/KO mice. Our studies with these mouse models will give new insight into the mechanism of short-term presynaptic plasticity and its role in neural circuit function, spatial learning, and memory. This information will be essential for understanding failure of spatial learning and memory in aging and neurodegenerative 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, structural, and cellular mechanisms of short-term synaptic plasticity, which takes place on the millisecond time scale and is important for encoding and transmitting information in neurons. We will relate these molecular and cellular changes to neural circuit functions and to mouse behavior. 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 #
5R01NS022625-32
Application #
9719903
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Churn, Severn Borden
Project Start
1985-09-09
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2021-03-31
Support Year
32
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Nanou, Evanthia; Lee, Amy; Catterall, William A (2018) Control of Excitation/Inhibition Balance in a Hippocampal Circuit by Calcium Sensor Protein Regulation of Presynaptic Calcium Channels. J Neurosci 38:4430-4440
Qian, Hai; Patriarchi, Tommaso; Price, Jennifer L et al. (2017) Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the ?2-adrenergic receptor in neurons. Sci Signal 10:
Patriarchi, Tommaso; Qian, Hai; Di Biase, Valentina et al. (2016) Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the ?2 adrenergic receptor. EMBO J 35:1330-45
Nanou, Evanthia; Scheuer, Todd; Catterall, William A (2016) Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to long-term potentiation and spatial learning. Proc Natl Acad Sci U S A 113:13209-13214
Tang, Lin; Gamal El-Din, Tamer M; Swanson, Teresa M et al. (2016) Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature 537:117-121
Southan, Christopher; Sharman, Joanna L; Benson, Helen E et al. (2016) The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucleic Acids Res 44:D1054-68
Nanou, Evanthia; Yan, Jin; Whitehead, Nicholas P et al. (2016) Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic CaV2.1 Ca2+ channels. Proc Natl Acad Sci U S A 113:1068-73
Nanou, Evanthia; Sullivan, Jane M; Scheuer, Todd et al. (2016) Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons. Proc Natl Acad Sci U S A 113:1062-7
Catterall, William A (2015) Finding Channels. J Biol Chem 290:28357-73
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

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