Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory.
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.
Moosmang
Sven
S
Institut für Pharmakologie und Toxikologie, Technische Universität München, 80802 Munich, Germany. moosmang@ipt.med.tu-muenchen.de
Haider
Nicole
N
Klugbauer
Norbert
N
Adelsberger
Helmuth
H
Langwieser
Nicolas
N
Müller
Jochen
J
Stiess
Michael
M
Marais
Else
E
Schulla
Verena
V
Lacinova
Lubica
L
Goebbels
Sandra
S
Nave
Klaus-Armin
KA
Storm
Daniel R
DR
Hofmann
Franz
F
Kleppisch
Thomas
T
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D001522:Behavior, Animal; D002070:Butadienes / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000172:deficiency / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D009570:Nitriles / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013037:Spatial Behavior / Q000502:physiology*; D019789:Tetraethylammonium / Q000494:pharmacology; D013997:Time Factors
D002070:Butadienes; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; C419385:L-type calcium channel alpha(1C); D009419:Nerve Tissue Proteins; D009570:Nitriles; D026902:Potassium Channel Blockers; D011500:Protein Synthesis Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; C113580:U 0126; C033652:postsynaptic density proteins; D019789:Tetraethylammonium; D000841:Anisomycin; D015763:2-Amino-5-phosphonovalerate