Neurological phenotype and synaptic function in mice lacking the CaV1.3 α subunit of neuronal L-type voltage-dependent Ca2+ channels

Clark, Natalie; Nagano, Norihiro; Kuenzi, Frederick M.; Jarolimek, Wolfgang; Huber, Irene; Walter, Doris; Wietzorrek, Georg; Boyce, Susan; Kullmann, Dimitri M.; Striessnig, Jörg; Seabrook, Guy R.

doi:10.1016/s0306-4522(03)00329-4

Cited by 70 publications

(79 citation statements)

References 23 publications

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“…CREBdependent transcription is generally regarded as an important step in the generation of the long-lasting forms of synaptic plasticity that are associated with learning and long-term memory (West et al, 2002;Thomas and Huganir, 2004). Interestingly, the induction of L-LTP, the long-lasting form of LTP that requires gene transcription and protein synthesis, depends mostly on Ca 2ϩ influx through LTCCs in hippocampal CA1 neurons (Moosmang et al, 2005;Raymond and Redman, 2006), again with a specific involvement of Ca v 1.2 channels (Clark et al, 2003;Moosmang et al, 2005).…”

Section: Physiological Potential Of Anomalous Ca V 12 Channels In Nementioning

confidence: 99%

“…This working hypothesis is based on the following: (1) the evidence that Ca v 1.2 and not Ca v 1.3 are the LTCCs specifically involved in the sustained Ras-MAPK-dependent CREB phosphorylation that is associated to CRE-mediated gene transcription (Moosmang et al, 2005) and in the gene transcription-dependent hippocampal L-LTP (Clark et al, 2003;Moosmang et al, 2005); (2) our present evidence that Ca v 1.2␣ 1 and not Ca v 1.3␣ 1 subunits are the pore-forming subunits of anomalous LTCCs; and (3) the peculiar biophysical properties of anomalous Ca v 1.2 channels that make them more suitable than Ca v 1.2 channels with cardiac-type gating to generate a large and sustained Ca 2ϩ influx in response to the postsynaptic voltage stimulus necessary for induction of LTCCdependent LTP.…”

Section: Physiological Potential Of Anomalous Ca V 12 Channels In Nementioning

confidence: 99%

“…Ca v 1.3 channels activate more rapidly and at more negative voltages than Ca v 1.2 (Koschak et al, 2001), which allows them to participate in the stabilization of upstate potentials and the control of neuronal firing (Hernandez-Lopez et al, 2000;Olson et al, 2005). In contrast, Ca v 1.2 is the major LTCC isoform responsible for activity-dependent gene transcription, hippocampal late-long-term potentiation (L-LTP) (Clark et al, 2003;Moosmang et al, 2005), and memory (Moosmang et al, 2005). Interaction with different intracellular proteins can result in different regulatory properties of Ca v 1.2 and Ca v 1.3 LTCCs (Olson et al, 2005;Zhang et al, 2005Zhang et al, , 2006.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Nature of Anomalous L-Type Calcium Channels in Mouse Cerebellar Granule Cells

Koschak¹,

Obermair²,

Pivotto³

et al. 2007

J. Neurosci.

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Section: Physiological Potential Of Anomalous Ca V 12 Channels In Nementioning

confidence: 99%

Section: Physiological Potential Of Anomalous Ca V 12 Channels In Nementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Nature of Anomalous L-Type Calcium Channels in Mouse Cerebellar Granule Cells

Koschak¹,

Obermair²,

Pivotto³

et al. 2007

J. Neurosci.

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“…Accordingly, a knock-out mouse model lacking the Ca v 1.3 channel showed neither a defect in hippocampus-dependent learning nor a defect in hippocampal LTP (Clark et al, 2003). To investigate their role in hippocampal LTP and memory formation, we generated a mouse line (Ca v 1.2 HCKO ) with an inactivation of the CACNA1C (Ca v 1.2) gene, mainly in the hippocampus and neocortex.…”

Section: Introductionmentioning

confidence: 99%

Role of Hippocampal Ca_v1.2 Ca²⁺Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

Moosmang¹,

Haider²,

Klugbauer³

et al. 2005

J. Neurosci.

393

357

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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 theCACNA1C(Cav1.2) gene in the hippocampus and neocortex (Cav1.2HCKO). 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.

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“…Ca V 1.2DHP ‫מ/מ‬ mice express functionally normal Ca V 1.2 channels at normal densities, but a point mutation in the DHP-binding pocket of the Ca V 1.2 ␣1 subunit eliminates their high sensitivity to DHP channel blockers as well as activators (Sinnegger-Brauns et al 2004). Ca V 1.3 ‫מ/מ‬ mice lack Ca V 1.3 channels (Platzer et al 2000) and express Ca V 1.2 channels at normal levels (Clark et al 2003).…”

mentioning

confidence: 99%

Role of L-type Ca²⁺channel isoforms in the extinction of conditioned fear

Busquet

Hetzenauer²,

Sinnegger-Brauns³

et al. 2008

Learn. Mem.

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Dihydropyridine (DHP) L-type Ca2+ channel (LTCC) antagonists, such as nifedipine, have been reported to impair the extinction of conditioned fear without interfering with its acquisition. Identification of the LTCC isoforms mediating this DHP effect is an essential basis to reveal their role as potential drug targets for the treatment of specific anxiety disorders. Ca V 1.2 and Ca V 1.3 are the predominant LTCCs in the mammalian brain. However, since no isoform-selective DHP blockers are available, their individual contribution to fear memory extinction is unknown. We used a novel mouse model expressing DHP-insensitive Ca V 1.2 LTCCs (Ca V 1.2DHP −/− mice) to address this question. In line with previous studies, wild-type (WT) mice treated with systemic nifedipine displayed markedly impaired fear extinction. This DHP effect was completely abolished in Ca V 1.2DHP −/− mice, indicating that it is mediated by Ca V 1.2, but not by Ca V 1.3 LTCCs. Supporting this conclusion, Ca V 1.3-deficient mice (Ca V 1.3 −/− ) showed extinction identical to the respective WT mice. The inhibition of fear extinction was not observed after intracerebroventricular (i.c.v.) application of different doses of nifedipine, suggesting that this effect is secondary to inhibition of peripheral Ca V 1.2 channels. The LTCC activator BayK, which lacks neurotoxic effects in Ca V 1.2DHP −/− mice, did not influence the extinction time course. In summary, we demonstrate that LTCC signaling through the Ca V 1.2 isoform of LTCCs interferes with fear memory extinction, presumably via a peripherally mediated mechanism. Activation of other LTCC isoforms (predominantly Ca V 1.3) is not sufficient to accelerate extinction of conditioned fear in mice.

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Neurological phenotype and synaptic function in mice lacking the CaV1.3 α subunit of neuronal L-type voltage-dependent Ca2+ channels

Cited by 70 publications

References 23 publications

Molecular Nature of Anomalous L-Type Calcium Channels in Mouse Cerebellar Granule Cells

Molecular Nature of Anomalous L-Type Calcium Channels in Mouse Cerebellar Granule Cells

Role of Hippocampal Ca_v1.2 Ca²⁺Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

Role of L-type Ca²⁺channel isoforms in the extinction of conditioned fear

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Neurological phenotype and synaptic function in mice lacking the CaV1.3 α subunit of neuronal L-type voltage-dependent Ca2+ channels

Cited by 70 publications

References 23 publications

Molecular Nature of Anomalous L-Type Calcium Channels in Mouse Cerebellar Granule Cells

Molecular Nature of Anomalous L-Type Calcium Channels in Mouse Cerebellar Granule Cells

Role of Hippocampal Cav1.2 Ca2+Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

Role of L-type Ca2+channel isoforms in the extinction of conditioned fear

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Role of Hippocampal Ca_v1.2 Ca²⁺Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

Role of L-type Ca²⁺channel isoforms in the extinction of conditioned fear