Phenotypes associated with this allele

• Allele Symbol: Cacna1a^tg
• Allele Name: tottering
• Allele ID: MGI:1856209
• Summary: 9 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cacna1a^tg/Cacna1a^tg	B6.D2-Cacna1a^tg/J	MGI:3700786
hm2	Cacna1a^tg/Cacna1a^tg	involves: 101 * C3H * C57BL/10 * DBA/2J	MGI:5634792
hm3	Cacna1a^tg/Cacna1a^tg	involves: C57BL/6J * DBA/2J	MGI:3700746
hm4	Cacna1a^tg/Cacna1a^tg	involves: DBA/2J	MGI:2655438
hm5	Cacna1a^tg/Cacna1a^tg	involves: DBA/2J * C57BL/10JGn	MGI:5634785
ht6	Cacna1a^tg-rol/Cacna1a^tg	involves: C3H * C57BL/6 * DBA/2J * SIII	MGI:4833694
cn7	Cacna1a^tg/Cacna1a^tm2.1Maag	involves: 129P2/OlaHsd * C57BL/6J * DBA/2J * FVB/N	MGI:5792057
cn8	Cacna1a^tg/Cacna1a^tm2.1Maag Tg(Pcp2-cre)2Mpin/0	involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6J * DBA/2J * FVB/N	MGI:5792055
cx9	Cacna1a^tg/Cacna1a^tg Tg(Pcp2-TAg)4Horr/0	B6J.Cg-Cacna1a^tg Tg(Pcp2-TAg)4Horr	MGI:5788005

Genotype
MGI:3700786

hm1

• Allelic Composition: Cacna1a^tg/Cacna1a^tg
• Genetic Background: B6.D2-Cacna1a^tg/J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

behavior/neurological

dystonia ( J:233263 )

• mice exhibit generalized dystonia

ataxia ( J:109231 )

• mice show ataxic behavior around 3-4 weeks of age

abnormal gait ( J:6154 )

• wobbly gait that is first apparent at 3-4 weeks of age and is most prominent in the hindquarters

seizures ( J:6154 )

• spontaneous motor seizures that occur one or more times per day in mice up to 3 months old but seem to decline in frequency during the life span an entire seizure

• an entire seizure lasts about 20-30 minutes and ends abruptly

increased susceptibility to pharmacologically induced seizures ( J:6154 )

• injection with subconvulsant doses of pentylenetetrazole evokes partial motor seizures and spike-wave discharges associated with myoclonic jerks in mutants but not wild-type mice

muscle

dystonia ( J:233263 )

• mice exhibit generalized dystonia

abnormal muscle electrophysiology ( J:233263 )

• abnormal hindlimb movements of mice with generalized dystonia are associated with increases in the amplitude of the electromyograph in both tibialis and gastrocnemius muscles

nervous system

seizures ( J:6154 )

• spontaneous motor seizures that occur one or more times per day in mice up to 3 months old but seem to decline in frequency during the life span an entire seizure

• an entire seizure lasts about 20-30 minutes and ends abruptly

increased susceptibility to pharmacologically induced seizures ( J:6154 )

• injection with subconvulsant doses of pentylenetetrazole evokes partial motor seizures and spike-wave discharges associated with myoclonic jerks in mutants but not wild-type mice

abnormal nervous system electrophysiology ( J:6154 )

• resting ECG shows abnormal bursts of bilaterally synchronous and symmetrical spike waves, 6-7 per second, over the cerebral hemispheres; abnormal bursts last from 0.3 to 10 seconds, occur hundreds of times per day, and can represent up to 10 % of resting ECG activity in an undisturbed adult

• ECG shows that subharmonic spike burst, with 3 spikes per second, is sometimes present

• ECG during seizures most commonly shows low-voltage, desynchronized activity interspersed with long runs of generalized theta waves

decreased excitatory postsynaptic current amplitude ( J:109231 )

• parallel fiber (PF) stimulation is less effective in eliciting EPSCs in ataxic mutants than in wild-type at stimulation intensities of 3-15 Volts

• EPSCs in mice aged 14-20 days (non-ataxic) show a 30% reduction in amplitude; mice aged 28-35 days (ataxic) show a 70% reduction in EPSC amplitude

• when the P/Q-type calcium channel blocker agatoxin is applied to brain slices, PF-EPSCs are reduced in amplitude by 60% compared to wild-type

abnormal paired-pulse inhibition ( J:109231 )

• PPI is observed at 50 msecond interpulse interval, but is reduced compared to wild-type or Cacna1^tg-rol homozygotes in young, non-ataxic mutants; PPI is further reduced in adult ataxic mice compared to young mutants

growth/size/body

decreased body weight ( J:6154 )

• adults weigh on average 7g less than wild-type mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
childhood electroclinical syndrome		DOID:0050704		J:6154
generalized dystonia		DOID:0050835		J:233263

Genotype
MGI:5634792

hm2

• Allelic Composition: Cacna1a^tg/Cacna1a^tg
• Genetic Background: involves: 101 * C3H * C57BL/10 * DBA/2J

behavior/neurological

abnormal motor capabilities/coordination/movement ( J:262 )

• mutant mice occasionally fall over

impaired limb coordination ( J:262 )

• toeing-out of hind feet is often noticeable before the gait becomes abnormal

• mutant mice often lean to one side

impaired swimming ( J:262 )

abnormal posture ( J:262 )

• the bodies of mutant mice are held closer to the ground

abnormal gait ( J:262 )

• Background Sensitivity: mutant mice are recognizeable by 2.5 weeks of age

abnormal maternal nurturing ( J:262 )

• due to effects of seizures

seizures ( J:262 )

• a seizure pattern develops in mutant mice by 3 weeks of age

• preceded by increased running with abrupt directional changes followed by no motor activity and increased respiration

• begin as early as 2 weeks of age as sporadic seizures

• have little effect on life span

sporadic seizures ( J:262 )

• begin as early as 2 weeks of age

• preceded by flattening of the sacral area with spastic abduction and extension of a hind limb

nervous system

seizures ( J:262 )

• a seizure pattern develops in mutant mice by 3 weeks of age

• preceded by increased running with abrupt directional changes followed by no motor activity and increased respiration

• begin as early as 2 weeks of age as sporadic seizures

• have little effect on life span

sporadic seizures ( J:262 )

• begin as early as 2 weeks of age

• preceded by flattening of the sacral area with spastic abduction and extension of a hind limb

reproductive system

reduced fertility ( J:262 )

• in both sexes due to impact of the neurological phenotype

Genotype
MGI:3700746

hm3

• Allelic Composition: Cacna1a^tg/Cacna1a^tg
• Genetic Background: involves: C57BL/6J * DBA/2J

nervous system

abnormal nervous system physiology ( J:221681 )

• anesthetized mice exhibit episodic, low-frequency oscillations throughout the cerebral cortex ranging between 0.035 and 0.11 Hz, which can spontaneously develop very high power

• the high power state is associated with increased cortical neuron firing variability

• treatment with tetrodotoxin, a voltage-gated sodium channel blocker, decreases the low-frequency oscillations

• blocking L-type calcium channels with diltiazem reduces the high-state of the low-frequency oscillations

• blocking nitric oxide signaling with L-NAME results in an increase in high-power low-frequency oscillations in the cerebral cortex

• treatment with acetazolamide or 4-aminopyridine decreases the high-power low-frequency oscillations

abnormal somatosensory cortex physiology ( J:221681 )

• mice exhibit a reduced response of activity in the contralateral barrel cortex to air puffs delivered to the c2 whisker, indicating a deficit in processing of sensory inputs into the somatosensory cortex

abnormal synaptic transmission ( J:221681 )

• the ipsilateral and contralateral responses to intracortical stimulation are lower in mutants than in wild-type mice

• blocking ionotropic (with DNQX and APV) or metabotropic glutamate receptors (with LY36738 and MPEP) results in high-power low-frequency oscillations in mutants but not wild-type mice, indicating that the low-frequency oscillations in the cerebral cortex are facilitated by a reduction in excitatory synaptic transmission

abnormal CNS synaptic transmission ( J:106959 )

• peak current densities of low voltage-activated (LVA) calcium channels in thalamocortical (TC) neurons at membrane potential of -50 mV are increased by 46% compared to control

• peak current densities of high voltage calcium channels (HVA) in TC neurons are increased compared to wild-type

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
episodic ataxia type 2		DOID:0050990	OMIM:108500	J:221681

Genotype
MGI:2655438

hm4

• Allelic Composition: Cacna1a^tg/Cacna1a^tg
• Genetic Background: involves: DBA/2J

behavior/neurological

abnormal gait ( J:262 )

• noticed after weaning

reproductive system

infertility ( J:262 )

• a trio mating, all homozygous, failed to produce offspring

Genotype
MGI:5634785

hm5

• Allelic Composition: Cacna1a^tg/Cacna1a^tg
• Genetic Background: involves: DBA/2J * C57BL/10JGn

behavior/neurological

abnormal gait ( J:262 )

• Background Sensitivity: some mutant mice may show a tottering gait by 4 weeks of age but all mutant mice showed coordination difficulties by 8 weeks of age

Genotype
MGI:4833694

ht6

• Allelic Composition: Cacna1a^tg-rol/Cacna1a^tg
• Genetic Background: involves: C3H * C57BL/6 * DBA/2J * SIII

mortality/aging

mortality/aging ( J:14882 )

N • normal life span

behavior/neurological

behavior/neurological phenotype ( J:14882 )

N • mutants do not exhibit epileptiform seizures that are seen in single homozygous Cacna1a^tg mice

abnormal locomotor behavior ( J:14882 )

ataxia ( J:14882 )

abnormal gait ( J:14882 )

• develop wobbly gait that is similar to that of single homozygous Cacna1a^tg-rol but more severe than in single homozygous Cacna1a^tg mice

nervous system

abnormal nervous system morphology ( J:14882 )

• neuromuscular disorder appears at 2 weeks of age, at a similar time frame as in single homozygous Cacna1a^tg-rol mice

Genotype
MGI:5792057

cn7

• Allelic Composition: Cacna1a^tg/Cacna1a^tm2.1Maag
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J * DBA/2J * FVB/N

behavior/neurological

dystonia ( J:233263 )

• mice injected with a lentivirus expressing cre recombinase into the midline or lateral cerebellum (to affect only 10-15% of the cerebellum) exhibit abnormal dystonic movements, with most isolated to a single body part, such as the hindlimb

• 90% of abnormal movements are tonic flexion or extension of the hindlimb, 8% are clonic movements of the head/neck and 2% are tonic flexion or extension of the trunk

muscle

dystonia ( J:233263 )

• mice injected with a lentivirus expressing cre recombinase into the midline or lateral cerebellum (to affect only 10-15% of the cerebellum) exhibit abnormal dystonic movements, with most isolated to a single body part, such as the hindlimb

• 90% of abnormal movements are tonic flexion or extension of the hindlimb, 8% are clonic movements of the head/neck and 2% are tonic flexion or extension of the trunk

abnormal muscle electrophysiology ( J:233263 )

• mice injected with a lentivirus expressing cre recombinase into the cerebellum exhibit an increase in electromyography amplitude of tibialis and gastrocnemius muscles

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
generalized dystonia		DOID:0050835		J:233263

Genotype
MGI:5792055

cn8

• Allelic Composition: Cacna1a^tg/Cacna1a^tm2.1Maag; Tg(Pcp2-cre)2Mpin/0
• Genetic Background: involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6J * DBA/2J * FVB/N

behavior/neurological

dystonia ( J:233263 )

• mice exhibit dystonia that is more severe than in single Cacna1a^tg homozygotes

• more than 95% of abnormal movements are either tonic or clonic

• mice show a small (5%) but significant shift towards increased head/neck postures than in single Cacna1a^tg homozygotes

muscle

dystonia ( J:233263 )

• mice exhibit dystonia that is more severe than in single Cacna1a^tg homozygotes

• more than 95% of abnormal movements are either tonic or clonic

• mice show a small (5%) but significant shift towards increased head/neck postures than in single Cacna1a^tg homozygotes

Genotype
MGI:5788005

cx9

• Allelic Composition: Cacna1a^tg/Cacna1a^tg; Tg(Pcp2-TAg)4Horr/0
• Genetic Background: B6J.Cg-Cacna1a^tg Tg(Pcp2-TAg)4Horr

behavior/neurological

ataxia ( J:233263 )

• mice exhibit gradually diminishing dystonia beginning at 10-13 weeks of age, leaving only a very mild ataxic gait

• postures of the head/neck and trunk abate first (with about 70% reduction in Purkinje cell density), with abnormal limb movements often persisting (with about 85% loss of Purkinje cells) and abating last (with about 90% loss of Purkinje cells)

nervous system

decreased Purkinje cell number ( J:233263 )

• Purkinje cell linear density decreases with age; Purkinje cells decrease rapidly in some mice while in others, loss is slower

• Purkinje cell loss appears to be random in cerebellar regions and does not correlate with affected body parts