Phenotypes Associated with This Genotype

Genotype
MGI:3624868

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

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

mortality/aging

mortality/aging ( J:15016 )

N • Background Sensitivity: viability is background dependent

cellular

increased apoptosis ( J:107924 )

• greater numbers of TUNEL-positive cells are detected in the granule cell layer of mutant mice than are found in wild-type (22.1 cells/section in mutants vs 4.6 cells/section in wild-type) at 20 days of age; there is no difference in numbers of apoptotic cells seen at 10 or 15 days

behavior/neurological

ataxia ( J:12735 , J:109231 )

• homozygous mice are identifiable between 10 and 14 days of age by a creeping or rolling gait (J:12735)

• mice show ataxic behavior around P10 (J:109231)

impaired limb coordination ( J:12735 )

• at 10-14 days of age, poor motor control of the hindlimbs can be observed

weakness ( J:12735 )

• mutants born on an inbred background are weak, but when crossed to produce congenic or co-isogenic lines, mice are more viable

abnormal nursing ( J:12735 )

♀ • females have a reduced ability to nurse pups

nervous system

abnormal brainstem morphology ( J:6553 )

• net weight of the brain stem is slightly reduced

abnormal cerebellum morphology ( J:12735 , J:107924 )

• in mutant mice, many apoptotic granule cells are seen in the cerebellum at 20 days of age (J:107924)

small cerebellum ( J:6553 )

• cerebellum weight is reduced to 75% of the controls

cerebellum atrophy ( J:107924 )

• regional atrophy is observed in the anterior lobe of the cerebellum in mutants

cerebellum hypoplasia ( J:15016 )

• size ratio of cerebellum to cerebrum in mutants is 0.35 in medial-dorsal aspect and 0.25 mid-sagitally compared to 0.40 and 0.30 respectively in wild-type, indicating cerebellar hypoplasia

abnormal CNS synaptic transmission ( J:109231 )

• application of AMPA to acutely dissociated Purkinje cells results in larger maximum inward current densities at lower AMPA concentrations than in wild-type or Cacna1^tg homozygotes

abnormal excitatory postsynaptic currents ( J:109231 )

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

prolonged excitatory postsynaptic current decay time ( J:164115 )

• decay time constant of climbing fiber-EPSCs (CF-EPSC) is significantly greater than in wild-type or Cacna1^tg homozygotes; rise times of CF-EPSCs of both mutant strains and wild-type are not significantly different

abnormal miniature excitatory postsynaptic currents ( J:109231 )

• miniature EPSCs have a larger decay time constant than wild-type or Cacna1^tg homozygotes

enhanced paired-pulse facilitation ( J:109231 )

• paired-pulse facilitation (PPF) magnitudes are significantly greater at 50 msec interpulse intervals than in wild-type Cacna1^tg homozygotes

reproductive system

reduced female fertility ( J:12735 )

♀ • females are fertile but do not breed well

reduced male fertility ( J:12735 )

♂ • males rarely breed

muscle

abnormal muscle electrophysiology ( J:164115 )

• muscles are very sensitive to low calcium, with contractions of flexor digitorium brevis muscles decreasing to about 40% in presence of 0.5 mM calcium

• flexor digitorium brevis muscles are more sensitive to low calcium than diaphragms

muscle weakness ( J:164115 )

• weakness of fast leg muscle

homeostasis/metabolism

decreased glutamic acid level ( J:6553 )

• concentration of glutamate is reduced to 86% of the control value in the cerebellum

increased glycine level ( J:6553 )

• concentration of glycine is increased in the cerebellum but not in other regions

increased taurine level ( J:6553 )

• concentration of taurine is increased in the cerebellum but not in other regions

abnormal metabolism ( J:15508 )

• thyrotropin releasing hormone (TRH) turnover is abnormally regulated in serotonergic neurons

• serotonin antagonists and serotonin receptor antagonists increase TRH content in the spinal cord instead of causing a decrease as in controls

decreased choline O-acetyltransferase activity ( J:6553 )

• choline acetyltransferase activity in the stratum and the frontal cortex is reduced

increased brain tyrosine 3-monooxygenase activity ( J:6553 )

• increase in activity of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, in the cerebellum, spinal cord, medulla, oblongata, thalamus, and hypothalamus

abnormal response/metabolism to endogenous compounds ( J:15508 )

• serotonin does not increase thyrotropin releasing hormone (TRH) content in the spinal cord as it does in control mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Lambert-Eaton myasthenic syndrome		DOID:0050214		J:164115