Phenotypes Associated with This Genotype

Genotype
MGI:4356170

• Allelic Composition: Atp1a3^Myk/Atp1a3⁺
• Genetic Background: B6NCr.129S1-Atp1a3^Myk

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

mortality/aging

premature death ( J:151948 )

• maximal tonic hindlimb extension is followed by death

behavior/neurological

abnormal behavior ( J:180250 , J:262367 )

• in the Porsolt forced swim test, mice spend a longer time active than wild-type mice, indicating increased motivation (J:180250)

• chronic lithium carbonate and valproic acid treatment reduces the behavioral abnormalities of mutants (J:180250)

• treatment with SL327, an inhibitor of ERK, and rostafuroxin, a compound that selectively displaces ouabain from the Na⁺,K⁺-ATPase reduces the behavioral abnormalities of mutants (J:180250)

• mice take longer to find a hidden platform and swim further compared with wild-type mice (J:262367)

• however, swim speed and floating is normal (J:262367)

abnormal sensitization to xenobiotic ( J:180250 )

• mice show increased sensitivity to low dose of D-amphetamine, showing increased ambulation, rearing, stereotypy, and circling behavior compared to wild-type mice

enhanced conditioned place preference behavior ( J:180250 )

• mice show a greater preference for reward compared to wild-type mice, consuming more sucrose solution relative to water, and initially consuming more sucrose solution before the choice test

impaired contextual conditioning behavior ( J:262367 )

abnormal habituation ( J:180250 )

• mice do not habituate hole-board exploration

• the amount of rearing increases over time in mutants but decreases over time in wild-type mice, suggesting impaired habituation

decreased anxiety-related response ( J:180250 )

• mice have greater locomotor activity in the center compared with wild-type mice, suggesting decreased anxiety-like behavior

• in the elevated plus maze, mice make more open-arm entries and exploratory head dips and show a preference for the open arms

• in the light-dark box, mice spend a higher percentage of time in the light and do not show a preference for the dark compartment

increased thigmotaxis ( J:262367 )

• in a Morris water maze due to reduced behavioral flexibility

abnormal response to novel object ( J:180250 )

• mice explore objects and nosepoke more frequently than wild-type mice in the novel-object test and hole-board test

abnormal startle reflex ( J:180250 )

• deficit in startle habituation

impaired coordination ( J:262367 )

• after training, mice on a balance beam exhibit more hind foot slips and take more time to cross than wild-type mice

abnormal gait ( J:180250 )

• walking path of mice is chaotic

increased locomotor activity ( J:180250 )

• in the novel open field, mice show hyperambulation, faster walking speed, and decreased freezing than wild-type mice

• mice are more hyperactive in the dark but not in response to light

prolonged circadian behavior period ( J:180250 )

• mice entrain to light and shown normal circadian periods in a 12 hour light:12 hour dark environment, however, when external zeitgebers are removed, mice show an extended endogenous circadian period of 25 hours because of an increase in activity compared to 23.5 hours in wild-type mice

abnormal sleep pattern ( J:180250 )

• mice have more wake time than wild-type mice across 24 hours

abnormal non-rapid eye movement sleep pattern ( J:180250 )

• REM sleep latency, as measured by the average duration of non-REM sleep that precedes entrance into REM sleep, is reduced

abnormal paradoxical sleep pattern ( J:180250 )

• in the light phase, mice show shorter non-REM sleep bout length

decreased frequency of paradoxical sleep ( J:180250 )

• in the light phase, mice show reduced number of REM sleep bouts

abnormal seizure response to inducing agent ( J:180250 )

• Background Sensitivity: while mutants backcrossed to C57BL/6NCr mice for 12 generations show increased susceptibility to stress-induced seizures, mutants backcrossed for 20 generations do not exhibit stress-induced seizure activity

environmentally induced seizures ( J:151948 )

• 3 of 9 mice exhibit immediate induced convulsive seizure upon shaking of their cage

• however, treatment with valproic acid reduces cage-shaking-induced seizures and transfection with the wild-type copy of the gene prevents cage-shaking-induced seizures

convulsive seizures ( J:151948 )

• at 4 weeks of age, mice exhibit spontaneous, recurrent behavioral convulsive seizures unlike wild-type mice

• seizures can be evoked by vestibular stress

• seizures begin with running and leaping, behavioral arrest, and Straub tail, are followed by whole body clonic jerking and falling, are accompanied by salivation, and occasionally progressed to maximal tonic hindlimb extension followed by death

• 3 of 9 mice exhibit immediate induced convulsive seizure upon shaking of their cage

abnormal spike wave discharge ( J:151948 )

• during behavioral seizures mice exhibit spike-waves characteristic of epileptic discharge

• vestibular stress induces intermittent sharp waves that increase in amplitude until generalized bilateral synchronous tonic-clonic seizure activity is observed

• superfusion with magnesium ion free artificial cerebrospinal fluid induces repeated synchronized ictal bursts in the CA3 and entorhinal cortex of more than 50% of slices unlike in similarly treated wild-type slices

• after theta burst stimulation, mice exhibit enhanced excitation-spike coupling compared to wild-type mice

nervous system

nervous system phenotype ( J:151948 )

N • mice exhibit normal synaptic transmission and synaptic plasticity

abnormal seizure response to inducing agent ( J:180250 )

• Background Sensitivity: while mutants backcrossed to C57BL/6NCr mice for 12 generations show increased susceptibility to stress-induced seizures, mutants backcrossed for 20 generations do not exhibit stress-induced seizure activity

environmentally induced seizures ( J:151948 )

• 3 of 9 mice exhibit immediate induced convulsive seizure upon shaking of their cage

• however, treatment with valproic acid reduces cage-shaking-induced seizures and transfection with the wild-type copy of the gene prevents cage-shaking-induced seizures

convulsive seizures ( J:151948 )

• at 4 weeks of age, mice exhibit spontaneous, recurrent behavioral convulsive seizures unlike wild-type mice

• seizures can be evoked by vestibular stress

• seizures begin with running and leaping, behavioral arrest, and Straub tail, are followed by whole body clonic jerking and falling, are accompanied by salivation, and occasionally progressed to maximal tonic hindlimb extension followed by death

• 3 of 9 mice exhibit immediate induced convulsive seizure upon shaking of their cage

abnormal spike wave discharge ( J:151948 )

• during behavioral seizures mice exhibit spike-waves characteristic of epileptic discharge

• vestibular stress induces intermittent sharp waves that increase in amplitude until generalized bilateral synchronous tonic-clonic seizure activity is observed

• superfusion with magnesium ion free artificial cerebrospinal fluid induces repeated synchronized ictal bursts in the CA3 and entorhinal cortex of more than 50% of slices unlike in similarly treated wild-type slices

• after theta burst stimulation, mice exhibit enhanced excitation-spike coupling compared to wild-type mice

abnormal temporal lobe morphology ( J:151948 )

• mice exhibit medial temporal sclerosis

abnormal hippocampus pyramidal cell morphology ( J:151948 )

• mice exhibit aberrant membranous whorls in the hippocampal pyramidal neurons unlike in wild-type mice

abnormal neuron physiology ( J:180250 )

• neurons exhibit higher resting intracellular free calcium and show prolonged glutamate-evoked intracellular free calcium transients

abnormal sensorimotor gating ( J:180250 )

decreased prepulse inhibition ( J:180250 )

• deficit in prepulse inhibition

growth/size/body

decreased body size ( J:151948 )

• at 9 weeks

decreased body weight ( J:151948 , J:262367 )

• at 9 weeks (J:151948)

• at 4 and 8 weeks in male and female mice (J:262367)

• Background Sensitivity: unlike mice maintained on a mix background, female mice on a C57BL/6NCr congenic background exhibit decreased both weight (J:262367)

homeostasis/metabolism

abnormal enzyme/coenzyme activity ( J:180250 )

• increase in total brain Na⁺,K⁺-ATPase activity

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
alternating hemiplegia of childhood		DOID:0050635	OMIM:104290 OMIM:614820 OMIM:PS104290	J:262367
bipolar disorder		DOID:3312		J:180250 , J:208021