Conditional forebrain deletion of the L-type calcium channel Ca_V1.2 disrupts remote spatial memories in mice

Abstract

To determine whether L-type voltage-gated calcium channels (L-VGCCs) are required for remote memory consolidation, we generated conditional knockout mice in which the L-VGCC isoform Ca V 1.2 was postnatally deleted in the hippocampus and cortex. In the Morris water maze, both Ca V 1.2 conditional knockout mice (Ca V 1.2 cKO ) and control littermates displayed a marked decrease in escape latencies and performed equally well on probe trials administered during training. In distinct contrast to their performance during training, Ca V 1.2 cKO mice exhibited significant impairments in spatial memory when examined 30 d after training, suggesting that Ca V 1.2 plays a critical role in consolidation of remote spatial memories.In recent years, a wealth of experimental evidence has emerged suggesting that activity-dependent changes in neuronal gene expression are regulated in large part by calcium influx via L-VGCCs. For example, calcium influx through L-VGCCs activates calcium-dependent calmodulin kinase IV and Ras/mitogenactivated kinase, which, in turn, phosphorylate the transcription factor CREB at serine 133 (Wu et al. 2001). Once phosphorylated, CREB becomes part of an active transcriptional complex that binds to cAMP-response element DNA sequences to regulate transcription of a number of gene products. Importantly, calciummediated activation of CREB has been implicated as a key subcellular signaling cascade in a wide range of behavioral processes including long-term memory consolidation (West et al. 2002;Deisseroth et al. 2003). Given the prominent role that L-VGCCs play in the activation of these signaling cascades, we have begun to examine the impact of altering L-VGCC function on memory consolidation. Consistent with the idea that L-VGCCs are a key component of this process, we have recently demonstrated that deletion of the L-VGCC isoform Ca V 1.3 produces a deficit in consolidation of contextual fear conditioning (McKinney and Murphy 2006). Here we report here that forebrain deletion of the alternate L-VGCC isoform Ca V 1.2 specifically disrupts remote spatial memories while sparing recently acquired spatial memories.To obtain regionally restricted deletion of Ca V 1.2, mice were generated using a BAC clone containing Cacna1c (the mouse Ca V 1.2 gene) obtained by screening a murine strain SV/129J BAC library (Genome Systems Inc.) with a probe representing exon 2 of Cacna1c. DNA fragments containing portions of Cacna1c were subcloned and mapped. Three adjacent XbaI fragments (4, 0.6, and 1.9 kb) were subcloned into a modified pflox vector (Chui et al. 1997) in which the thymidine kinase (TK) cassette had been removed. The MC1-TK cassette (Thomas and Capecchi 1987) was introduced at the junction of the 3Ј homology unit and the plasmid vector. The final targeting vector (Fig. 1A) had 4 kb of 5Ј homology, a loxP site introduced into intron 1, a 0.6-kb region containing exon 2, a loxP-Neo-loxP cassette introduced into intron 2, 1.9 kb of 3Ј homology, and the MC1-TK cassette.The targeting vector was linearized and e...

L-type voltage-gated calcium channels in conditioned fear: A genetic and pharmacological analysis

“…The conditional deletion of Ca v 1.2 in the neocortex and hippocampus of Ca v 1.2 cKO mice, two brain regions critically involved in fear conditioning and its extinction (Maren 2001;Myers and Davis 2006), has previously been described (White et al 2008). We have subsequently conducted a series of experiments to examine the expression pattern of cre-recombinase and to determine the extent of the deletion of Ca v 1.2 in the basolateral amygdaloid complex (BLA; composed of the lateral, basolateral, and basomedial amygdaloid nuclei).…”

“…We have previously demonstrated that these mice have disrupted remote spatial memories (White et al 2008). Here we demonstrate that conditional deletion of Ca v 1.2 does not disrupt consolidation of conditioned fear.…”

The genomics of schizophrenia: update and implications

“…The voltagegated L-type calcium channel is formed from the multimerization of the pore-forming α 1c subunit (encoded by CACNA1C), which directly interacts with the intracellular β 2 subunit (encoded by CACNB2), and a third extracellular membrane anchored α 2 δ subunit (71, 72). Calcium channels have been extensively studied in neuroscience and are critically important for learning, memory, and synaptic plasticity (73)(74)(75). Several Mendelian disorders result from deleterious mutations in calcium channel subunits.…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Hippocampal function depends mainly on Ca V 1.2. This isoform is required for hippocampal spatial memory formation (Moosmang et al, 2005a;White et al, 2008) for protein synthesisdependent, NMDA receptor-independent late-phase long-term potentiation (LTP) in CA3-CA1 synapses, and for activation of the microtubule-associate protein kinase/cAMP/calcium response element binding protein (CREB) signaling cascade (Moosmang et al, 2005a). In contrast with Ca V 1.2, Ca V 1.3 does not contribute to CA3-CA1 hippocampal LTP and the spatial memory encoding in the Morris water maze appeared normal in Ca V 1.3-deficient mice (McKinney and Murphy, 2006).…”