Phenotypes Associated with This Genotype

Genotype
MGI:2652947

• Allelic Composition: Bsn^tm1Gund/Bsn^tm1Gund
• Genetic Background: Not Specified

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

mortality/aging

premature death ( J:82241 )

• homozygotes are viable and morphologically normal at birth

• however, ~50% die during the first 6 months of life from epileptic seizures

nervous system

increased susceptibility to pharmacologically induced seizures ( J:82241 )

• in response to pharmacologic blockade of glutamate receptors by MK-801, a number of homozygotes develop severe seizures with paroxysmal epileptiform spiking in hippocampal and cortical EEGs, not observed in wild-type mice

convulsive seizures ( J:82241 )

• homozygotes develop pronounced spontaneous epileptic seizures (up to 4 events/day)

clonic seizures ( J:82241 )

• typically, homozygotes show loss of righting reflex and generalized clonic convulsions, followed by rearing and bilateral forelimb clonus

• convulsive activity duration varies between 18 and 33 sec and is followed by postical immobility for 30-60 sec

• mouth clonus is partly noted at the end of generalized seizure activity

myoclonus ( J:82241 )

• some homozygotes exhibit myoclonic seizures independently of generalized clonic seizures

abnormal inner hair cell synaptic ribbon morphology ( J:114223 , J:167745 )

• at 3 and 8 weeks, all homozygotes contain numerous IHC cisternal aggregates whereas only a few isolated cisterns are found in wild-type littermates (2 of 7) (J:114223)

• membrane profiles resemble cisterns when they are distant from floating or anchored ribbons but are similar to vesicles when close to ribbons (J:114223)

• inner hair cell synapses contain fewer ribbon-occupied synapses than in wild-type mice (J:167745)

• hair cell synapses exhibit reduced membrane-proximal vesicles compared to in wild-type mice (J:167745)

• inner hair cells synapses exhibit fewer calcium channel and altered shape of calcium channel clusters compared to in wild-type mice (J:167745)

absent active-zone-anchored inner hair cell synaptic ribbon ( J:114223 )

• at 3 and 8 weeks, mutant IHCs display ribbon-deficient synapses at the active zone, which is abnormally occupied by tubular and cisternal membrane profiles

decreased cochlear nerve compound action potential ( J:114223 )

• at 8 weeks, auditory brainstem responses evoked by supra-threshold clicks (80 dB) show a reduced and delayed first peak, indicating impaired compound action potential in the spiral ganglion

• notably, distortion product otoacoustic emissions remain unaffected

abnormal retina rod cell morphology ( J:187689 )

• ribbon synapses float in the presynaptic cytoplasm and lose the typical horseshoe shaped form, the presynaptic arciform density is disassembled and the postsynaptic accumulation of the Ca2+ channel pore-forming unit Cacna1s is no longer detected

abnormal synaptic vesicle number ( J:114223 )

• loss of active-zone-anchored synaptic ribbons reduces the presynaptic readily releasable vesicle pool whereas endocytic membrane retrieval remains intact

abnormal brain wave pattern ( J:82241 )

• homozygotes develop severe seizures with paroxysmal epileptiform spiking in hippocampal and cortical EEGs in response to pharmacological blockade of glutamate receptors

abnormal somatic nervous system physiology ( J:114223 )

• at 8 weeks, homozygotes exhibit a reduction of sound-evoked activation of spiral ganglion neurons (SGNs), not due to defects in OHC amplification

abnormal cochlear inner hair cell physiology ( J:114223 , J:167745 )

• at 8 weeks, patch-clamp analysis of presynaptic IHCs shows a significant reduction of fast exocytosis (as shown by membrane capacitance increments in response to short stimuli) and of Ca²⁺ current (J:114223)

• both exocytosis of the hair cell releasable vesicle pool and the number of synchronously activated SGNs co-vary with the number of anchored ribbons during development (J:114223)

• inner hair cell synapses exhibit reduced calcium influx and readily releasable pool exocytosis compared to in wild-type mice (J:167745)

• inner hair cell synapses exhibit reduced synaptic calcium influx due to fewer channels and lower open probability compared to in wild-type mice (J:167745)

• inner hair cell synapses exhibit reduced exocytosis compared to in wild-type mice (J:167745)

• inner hair cell synapses exhibit slowed vesicle replenishment compared to in wild-type mice (J:167745)

• however, calcium influx-exocytosis coupling is intact (J:167745)

abnormal synaptic transmission ( J:114223 )

• at 8 weeks, homozygotes exhibit an auditory neuropathy associated with a defect in synchronous synaptic transmission at the ribbon synapse of cochlear inner hair cells

abnormal CNS synaptic transmission ( J:82241 )

• homozygotes display normal synapse structure in various brain regions, with no significant differences in synapse density, synaptic vesicle (SV) density in the proximal zone, extension of the active zone or number of docked SVs in the stratum radiatum of the hippocampal CA1 region relative to wild-type mice

• however, homozygotes show reduced synaptic transmission due to inactivation of a significant number of excitatory (glutamergic) synapses associated with a 30-50% reduction in synaptic strength and an overall reduction of fusion-competent SVs

• the remaining active synapses are largely normal with respect to quantal size, vesicular or synaptic release probabilities, vesicular refilling kinetics and short-term plasticity

• whole-cell patch recordings from mutant CA1 pyramidal cells exhibit a shift of input-output properties, expressed as a markedly reduced excitability over a broad range of stimulation intensities

decreased synaptic depression ( J:82241 )

• in the presence of CPP-induced blockade of NMDA receptors, homozygotes show a significantly reduced synaptic depression during long trains of low-frequency stimulation (LFS, 900 stimulus pairs at 2 Hz; 50 ms IPI) relative to wild-type mice; however, long-term depression is unaffected

behavior/neurological

increased susceptibility to pharmacologically induced seizures ( J:82241 )

• in response to pharmacologic blockade of glutamate receptors by MK-801, a number of homozygotes develop severe seizures with paroxysmal epileptiform spiking in hippocampal and cortical EEGs, not observed in wild-type mice

impaired righting response ( J:82241 )

• in response to a low, non-toxic dose of the NMDA antagonist MK-801, most homozygotes show a reduced righting reflex, not observed in wild-type mice

ataxia ( J:82241 )

• in response to a low, non-toxic dose of MK-801, homozygotes display significantly higher cumulative scores for ataxia relative to wild-type mice

convulsive seizures ( J:82241 )

• homozygotes develop pronounced spontaneous epileptic seizures (up to 4 events/day)

clonic seizures ( J:82241 )

• typically, homozygotes show loss of righting reflex and generalized clonic convulsions, followed by rearing and bilateral forelimb clonus

• convulsive activity duration varies between 18 and 33 sec and is followed by postical immobility for 30-60 sec

• mouth clonus is partly noted at the end of generalized seizure activity

myoclonus ( J:82241 )

• some homozygotes exhibit myoclonic seizures independently of generalized clonic seizures

muscle

myoclonus ( J:82241 )

• some homozygotes exhibit myoclonic seizures independently of generalized clonic seizures

hearing/vestibular/ear

abnormal inner hair cell synaptic ribbon morphology ( J:114223 , J:167745 )

• at 3 and 8 weeks, all homozygotes contain numerous IHC cisternal aggregates whereas only a few isolated cisterns are found in wild-type littermates (2 of 7) (J:114223)

• membrane profiles resemble cisterns when they are distant from floating or anchored ribbons but are similar to vesicles when close to ribbons (J:114223)

• inner hair cell synapses contain fewer ribbon-occupied synapses than in wild-type mice (J:167745)

• hair cell synapses exhibit reduced membrane-proximal vesicles compared to in wild-type mice (J:167745)

• inner hair cells synapses exhibit fewer calcium channel and altered shape of calcium channel clusters compared to in wild-type mice (J:167745)

absent active-zone-anchored inner hair cell synaptic ribbon ( J:114223 )

• at 3 and 8 weeks, mutant IHCs display ribbon-deficient synapses at the active zone, which is abnormally occupied by tubular and cisternal membrane profiles

abnormal cochlear inner hair cell physiology ( J:114223 , J:167745 )

• at 8 weeks, patch-clamp analysis of presynaptic IHCs shows a significant reduction of fast exocytosis (as shown by membrane capacitance increments in response to short stimuli) and of Ca²⁺ current (J:114223)

• both exocytosis of the hair cell releasable vesicle pool and the number of synchronously activated SGNs co-vary with the number of anchored ribbons during development (J:114223)

• inner hair cell synapses exhibit reduced calcium influx and readily releasable pool exocytosis compared to in wild-type mice (J:167745)

• inner hair cell synapses exhibit reduced synaptic calcium influx due to fewer channels and lower open probability compared to in wild-type mice (J:167745)

• inner hair cell synapses exhibit reduced exocytosis compared to in wild-type mice (J:167745)

• inner hair cell synapses exhibit slowed vesicle replenishment compared to in wild-type mice (J:167745)

• however, calcium influx-exocytosis coupling is intact (J:167745)

abnormal auditory brainstem response ( J:114223 )

• at 8 weeks, homozygotes exhibit distortion of auditory brainstem response waveforms and increased thresholds

• however, homozygotes are not completely deaf, indicating that the remaining fast exocytosis and the presence of slow exocytosis sustain some residual auditory signaling

decreased cochlear nerve compound action potential ( J:114223 )

• at 8 weeks, auditory brainstem responses evoked by supra-threshold clicks (80 dB) show a reduced and delayed first peak, indicating impaired compound action potential in the spiral ganglion

• notably, distortion product otoacoustic emissions remain unaffected

impaired hearing ( J:167745 )

• mild

vision/eye

abnormal retina rod cell morphology ( J:187689 )

• ribbon synapses float in the presynaptic cytoplasm and lose the typical horseshoe shaped form, the presynaptic arciform density is disassembled and the postsynaptic accumulation of the Ca2+ channel pore-forming unit Cacna1s is no longer detected

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
epilepsy		DOID:1826		J:82241