Abstract
Current knowledge about the molecular mechanisms of NMDA receptor (NMDAR)-independent long-term potentiation (LTP) in the hippocampus and its function for memory formation in the behaving animal is limited. NMDAR-independent LTP in the CA1 region is thought to require activity of postsynaptic L-type voltage-dependent Ca2+ channels (Cav1.x), but the underlying channel isoform remains unknown. We evaluated the function of the Cav1.2 L-type Ca2+ channel for spatial learning, synaptic plasticity, and triggering of learning-associated biochemical processes using a mouse line with an inactivation of the CACNA1C (Cav1.2) gene in the hippocampus and neocortex (Cav1.2(HCKO)). This model shows (1) a selective loss of protein synthesis-dependent NMDAR-independent Schaffer collateral/CA1 late-phase LTP (L-LTP), (2) a severe impairment of hippocampus-dependent spatial memory, and (3) decreased activation of the mitogen-activated protein kinase (MAPK) pathway and reduced cAMP response element (CRE)-dependent transcription in CA1 pyramidal neurons. Our results provide strong evidence for a role of L-type Ca2+ channel-dependent, NMDAR-independent hippocampal L-LTP in the formation of spatial memory in the behaving animal and for a function of the MAPK/CREB (CRE-binding protein) signaling cascade in linking Cav1.2 channel-mediated Ca2+ influx to either process.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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2-Amino-5-phosphonovalerate / pharmacology
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Animals
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Anisomycin / pharmacology
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Behavior, Animal
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Butadienes / pharmacology
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Calcium Channels, L-Type / deficiency
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Calcium Channels, L-Type / physiology*
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Dose-Response Relationship, Drug
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Dose-Response Relationship, Radiation
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Drug Interactions
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Electric Stimulation / methods
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Fluorescent Antibody Technique / methods
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Gene Expression Regulation / drug effects
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Hippocampus / cytology
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Hippocampus / physiology*
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Membrane Potentials / radiation effects
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Memory / physiology*
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Mice
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Mice, Knockout
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Nerve Tissue Proteins / drug effects
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Nerve Tissue Proteins / physiology
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Neuronal Plasticity / drug effects
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Neuronal Plasticity / physiology*
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Neuronal Plasticity / radiation effects
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Nitriles / pharmacology
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Patch-Clamp Techniques / methods
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Potassium Channel Blockers / pharmacology
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Protein Synthesis Inhibitors / pharmacology
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Pyramidal Cells / drug effects
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Pyramidal Cells / physiology
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Pyramidal Cells / radiation effects
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Receptors, N-Methyl-D-Aspartate / physiology*
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Spatial Behavior / physiology*
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Tetraethylammonium / pharmacology
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Time Factors
Substances
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Butadienes
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Calcium Channels, L-Type
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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L-type calcium channel alpha(1C)
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Nerve Tissue Proteins
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Nitriles
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Potassium Channel Blockers
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Protein Synthesis Inhibitors
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Receptors, N-Methyl-D-Aspartate
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U 0126
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postsynaptic density proteins
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Tetraethylammonium
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Anisomycin
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2-Amino-5-phosphonovalerate