This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, mutation of the CACNA1C gene has been found to be associated with Timothy syndrome, patients which all also fall under the category of ASD. In addition, several studies have shown a genetic association between the CACNA1C gene and schizophrenia as well as bipolar disorder.
Molecular Function
This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.
Involvement of Calcium-Dependent Pathway and β Subunit-Interaction in Neuronal Migration and Callosal Projection Deficits Caused by the Cav1.2 I1166T Mutation in Developing Mouse Neocortex
The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome
Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A neo cassette preceded by stop codons inserted into Exon 3 of Cacna1c in the reverse direction of transcription.
Allele Type: Knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A Neo and HSV-TK cassette, with two flanking loxP sites inserted into the intron between exons 13 and 14; a third loxP site placed into the intron between exons 15 and 16. Excised in vitro by Cre-mediated recombination prior to germline transmission.
Allele Type: Knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The targeting construct consisted of a 10.3-kb genomic including T1066Y mutation in exon 24 and a neo cassette with two loxP elements in parallel orientation and driven by the phosphoglycerate kinase promoter, inserted into the intron sequence 280-bp upstream of exon 24. This mutation eliminates the contribution of this channel type to dihydropyridine effects.
Allele Type: LOF Knockin
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6J
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 14 and 15, encoding IIS5 and IIS6 transmembrane segments and the pore loop in domain II, of the Cacna1c gene using Nex-Cre in excitatory (glutamatergic) neurons of the in forebrain starting E11.5
Allele Type: Conditional loss-of-function
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 14-15 of the Cacna1c gene mice using Nestin-Cre, in neuronal, glial and other cell types in the central and peripheral nervous system
Allele Type: Conditional loss-of-function
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Heterozygous Timothy Syndrome Type 2 mouse model of ASD (TS2-neo, B6.Cg-Cacna1ctm2Itl/J) contains the gain of function allele bearing a single nucleotide polymorphism (G406R) in exon 8/8A of Cacna1c that results in a functional channel with disrupted inactivation and an extremely high penetrance of ASD, accompanied by an unexcised neomycin-resistance cassette that suppresses mutant channel expression, resulting in normal survival of mice. Authors used male TS2-neo mice for breeding to avoid potential disruptions in maternal behavior in TS2-neo females that would confound subsequent experimental results. A pre-adolescent time period was used for experimentations as this is more relevant to the corresponding human condition (Timothy Syndrome) that manifests in childhood.
Allele Type: ASD GOF mutation
Strain of Origin: C57BL/6J:129Sv
Genetic Background: C57BL/6J
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: In-Genious Targeting Laboratory, Stony Brook, NY (PMID 21878566)
Model Type:
Genetic
Model Genotype:
Compound heterozygous
Mutation:
CNS-specific Cacna1c knockout mice were obtained by initially breeding Cacna1c^lox/lox (flanking exons 15 and 15) mice with Nestin-Cre mice. Subsequently Cacna1c^lox/lox mice were bred to Cacna1c^+/-:Nestin-Cre mice to obtain Cacna1c^+/lox:Nestin-Cre (CNS heterozygous used as controls) and Cav1.2^CNS-CKO (Cacna1c^-/lox:Nestin-Cre, compound heterozygous, with full deletion of Cacna1c in the CNS). .
Allele Type: Conditional knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: Not Specified
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Cacna1c^-/lox mice were obtained from breeding Cacna1c^lox/lox mice to Cacna1c^-/+:Nestin-Cre mice.
Allele Type: Knockout
Strain of Origin: Not Specified
Genetic Background: Not Specified
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source:
Model Type:
Multifactorial
Model Genotype:
Heterozygous
Mutation:
Cacna1c^-/lox mice were obtained from breeding Cacna1c^lox/lox mice to Cacna1c^-/+:Nestin-Cre mice and sujected to chronic social defeat stress (CSDS). Experimental mice (male mice between 3-4 months of age) were submitted to CSDS for 21 consecutive days. They were introduced into the home cage of a dominant CD1 resident for no longer than 5 min, and were subsequently defeated. Following defeat, animals spent 24 hours in the same cage, which was separated via a perforated steel partition, enabling sensory but not physical contact. Every day experimental mice were exposed to a new unfamiliar resident. Defeat encounters were randomized, with variations in starting time in order to decrease the predictability to the stressor and minimize habituation effects.
Allele Type: Conditional knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: Not Specified
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source:
Model Type:
Multifactorial
Model Genotype:
Homozygous
Mutation:
Cacna1c CKO mice, with loss of the gene from forebrain excitatory projection neurons in adulthood (M_CACNA1C_9_CKO_HM), were subjected to chronic social defeat stress (CSDS).male mice between 3-4 months of age) were submitted to CSDS for 21 consecutive days. They were introduced into the home cage of a dominant CD1 resident for no longer than 5 min, and were subsequently defeated. Following defeat, animals spent 24 hours in the same cage, which was separated via a perforated steel partition, enabling sensory but not physical contact. Every day experimental mice were exposed to a new unfamiliar resident. Defeat encounters were randomized, with variations in starting time in order to decrease the predictability to the stressor and minimize habituation effects.
Allele Type: Multifactorial
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: Not Specified
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source:
Model Type:
Multifactorial
Model Genotype:
Heterozygous
Mutation:
Cacna1c het CKO from forebrain excitatory projection neurons in adulthood (M_CACNA1C_8_CKO_HT) were subjected to chronic social defeat stress(CSDS). Experimental mice (male mice between 3-4 months of age) were submitted to CSDS for 21 consecutive days. They were introduced into the home cage of a dominant CD1 resident for no longer than 5 min, and were subsequently defeated. Following defeat, animals spent 24 hours in the same cage, which was separated via a perforated steel partition, enabling sensory but not physical contact. Every day experimental mice were exposed to a new unfamiliar resident. Defeat encounters were randomized, with variations in starting time in order to decrease the predictability to the stressor and minimize habituation effects.
Allele Type: Multifactorial
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of exons 14-15 of the Cacna1c gene mice using CamkII-CreERT2, in excitatory neurons of the forebrain with tamoxifen -containing food administered postnatal weeks 11-13,after which it was washed out for two weeks with regular chow during which behavioral experiments were conducted
Allele Type: Conditional loss-of-function
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: Not Specified
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 14-15 of the Cacna1c gene mice using CamkII-CreERT2, in excitatory neurons of the forebrain with tamoxifen -containing food administered postnatal weeks 11-13,after which it was washed out for two weeks with regular chow during which behavioral experiments were conducted
Allele Type: Conditional loss-of-function
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: Not Specified
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source:
Description: Mutant mice show decrease in ltp compared with control mice, one hour after a 100 hz tetanus stimulation.
Exp Paradigm: Hippocampal ltp was measured at the schaffer collateral-ca1 synapses.
Description: Mutant mice spent less time immobile and increased active stress-coping behavior in the forced swim test, compared to controls.
Exp Paradigm: NA
Description: Mutants show cacna1c ablation in forebrain glutamatergic neurons was largely restricted to vglut1-expressing cells, including the ctx, ca1/2/3 of the hip, and lateral and basolateral amygdala. mutants also show deletion of cacna1c mrna expression in the dentate gyrus and within a few neurons of the latero-dorsal thalamus and medial parts of the thalamus, central nucleus of the amygdala and the geniculate nucleus, compared to controls.
Exp Paradigm: NA
Description: Mutants show hyperlocomotion, measured in distance travelled, during the last segments of the open field test, compared to controls, although total distance travelled was not changed.
Exp Paradigm: NA
Description: Decreased hebbian long term potentiation in brain slices after administration of phtx
Exp Paradigm: Current clamp mode recordings at the thalamo input synapses after administration of 10 micromolar phtx, a blocker of cp-ampar
Description: Increased hebbian long term potentiation demonstrated by elevated epsp slope values after ltp induction in lateral amygdala slices after administration of isradipine
Exp Paradigm: Current clamp mode recordings at the thalamo input synapses after administration of isradipine
Description: Increased epsc amplitude at -70 mv at the thalamo-amygdala synapse
Exp Paradigm: Whole-cell patch-clamp recordings of thalamo-amygdala synapses
Description: Decreased hebbian long term potentiation in lateral amygdala slices
Exp Paradigm: Current clamp mode recordings at the thalamo-amygdala neurons
Description: Decreased synaptic transmission demonstrated by no effect of isradipine on ba2+ inward current in pyramidal cells of amygdala slices
Exp Paradigm: Ba2+ current recordings in pyramidal neurons of lateral amygdala
Description: Mutant mice spent less time immobile and increased active stress-coping behavior in the forced swim test, compared to controls.
Exp Paradigm: NA
Description: Mutants spend less time in the lit zone and enter the lit zone fewer times compared to controls. mutants show no change in latency to enter the lit zone.
Exp Paradigm: NA
Description: Decreased levels of cacna1c protein expression in hippocampus, neocortex, cerebellum, olfactory bulb, and amygdala
Exp Paradigm: Cacna1c protein expression
Description: In the assessments made by smartcube, the discrimination index for cacna1c het mutants (differentiating them from controls), was strongly affected by decreased abrdupt movements or locomotion bursts
Exp Paradigm: NA
Description: Cacna1c het mutant males exposed to the urine of an estrus female, in the of arena, mutant males exposed to the urine of an estrus female, in the of arena, have shorter distance travelled compared to controls
Exp Paradigm: NA
Description: Ts-2 neo mice show a decrease in 5ht turnover in the amygdala compared to controls.
Exp Paradigm: Forebrain tissue content of monoamines and their metabolites, including serotonin (5-ht), the 5-ht metabolite 5-hydroxyindoleacetic acid (5-hiaa), norepinephrine, dopamine, and the dopamine metabolites dopac and hva, were measured. 5ht turnover was measured by the ratio of 5-hiaa by 5-ht.
Description: Ts-2 neo mice show increased sert expression in the dorsal striatum compared to controls, indicating increased axon density.
Exp Paradigm: Serotonin transporter (sert) was used to measure axon density
Neuronal activation following behavioral stimulation: c-fos levels3
Increased
Description: Saline-treated ts2-neo mice show increased number of fos-positive 5-ht neurons in the caudal-ventral drn compared to wildtype controls after forced swim test.
Exp Paradigm: Fos/tph2 colabeling experiments
Description: Cacna1c het mice show reduced preference for mouse occupied cage ('corral') than the empty cage, in a prolonged version of the three-chamber social approach task lasting for about 4 hours
Exp Paradigm: Three chamber test
Description: Cacna1c het pups have significantly reduced time periods of usv calls following separation over the first 12 days (tested alternate days) of life
Exp Paradigm: Pup separation test
Description: Ts2-neo mice swim more during the 15-minute fst compared to their wt counterparts, indicating disrupted regulation of ascending 5-ht system activity, including feedback-inhibition of the drn 5-ht neurons.
Exp Paradigm: Active coping (horizontal movement through tank with both hind paws moving in synchrony) and passive coping (minimal horizontal movement and minimal hind paw movements required to keep the head above the water) behaviors were scored
Description: Increased latency to enter novel environment, decreased time spent in novel environment
Exp Paradigm: Addition of annex to home cage, connected by tube. annex test was 15 minutes, after 5 days in home cage.
Description: Cacna1c het mutant males exposed to the urine of estrus female display increased anxiety as they spend less time in the center of the open field arena
Exp Paradigm: NA
Description: Ts2-neo mice show increased dopac levels in the orbitofrontal cortex compared to controls.
Exp Paradigm: Forebrain tissue content of monoamines and their metabolites, including serotonin (5-ht), the 5-ht metabolite 5-hydroxyindoleacetic acid (5-hiaa), norepinephrine, dopamine, and the dopamine metabolites dopac and hva, were measured
Description: Mutants show hyperlocomotion, measured in distance travelled, during the last segments of the open field test, compared to controls, although total distance travelled was not changed.
Exp Paradigm: NA
Description: Mutant mice spent less time immobile and increased active stress-coping behavior in the forced swim test, compared to controls.
Exp Paradigm: NA
Description: Mutants spend less time in the lit zone and enter the lit zone fewer times compared to controls. mutants show no change in latency to enter the lit zone.
Exp Paradigm: NA
Description: Chronically stressed mutant mice displayed drastically reduced locomotion throughout the entire test duration compared to controls.
Exp Paradigm: NA
Description: Under chronically stressed conditions, mutants show decrease in thymus tissue weight upon chronic stress induction, compared to controls.
Exp Paradigm: NA
Description: Under chronically stressed conditions, mutant mice show deterioration of fur state with progression of chronic social defeat stress compared to controls.
Exp Paradigm: Mice were subjected to 3 weeks chronic social defeat stress.
Description: Under chronically stressed conditions, mutants show increase in adrenal tissue weight upon chronic stress, compared to controls.
Exp Paradigm: NA
Description: Chronically stressed mutant mice spent less time in the lit zone, entered the lit zone fewer times and showed increased latency to enter the lit zone, compared to controls.
Exp Paradigm: NA
Description: Under chronically stressed conditions, mutants show decrease in thymus tissue weight upon chronic stress induction, compared to controls.
Exp Paradigm: NA
Description: Under chronically stressed conditions, mutant mice show deterioration of fur state with progression of chronic social defeat stress compared to controls.
Exp Paradigm: Mice were subjected to 3 weeks chronic social defeat stress.
Description: Under chronically stressed conditions, mutants show increase in adrenal tissue weight upon chronic stress, compared to controls.
Exp Paradigm: NA
Description: Under chronically stressed conditions, mutant mice showed increase in time spent in the lit zone and increase in number of light zone entries compared to controls. under chronically stressed conditions, mutant mice showed no change in latency to enter the lit zone compared to controls.
Exp Paradigm: NA
Description: Under chronically stressed conditions, mutants show decrease in thymus tissue weight upon chronic stress induction, compared to controls.
Exp Paradigm: NA
Description: Under chronically stressed conditions, mutant mice show deterioration of fur state with progression of chronic social defeat stress compared to controls.
Exp Paradigm: Mice were subjected to 3 weeks chronic social defeat stress.
Description: Under chronically stressed conditions, mutants show increase in adrenal tissue weight upon chronic stress, compared to controls.
Exp Paradigm: NA
Description: Under chronically stressed conditions, mutant mice showed increase in time spent in the lit zone compared to controls. under chronically stressed conditions, mutant mice showed no change in latency to enter the lit zone or in number of light zone entries compared to controls.
Exp Paradigm: NA
Description: Under chronically stressed conditions, mutant mice showed decrease in number of inner zone entries, compared to controls.
Exp Paradigm: NA
Description: Mutants show increased accuracy in reaching the target during the relearning phase the week after learning but not 30 days after relearning, compared to controls.
Exp Paradigm: NA
Description: Mutant mice show cacna1c mrna deletion in vglut1-positive neurons of the lateral and basolateral amygdala, as well as the entire cerebral ctx and hip, compared to controls.
Exp Paradigm: NA
