Phenotypes Associated with This Genotype

Genotype
MGI:8235172

• Allelic Composition: Gabrb3^tm1.1Rmac/Gabrb3⁺
• Genetic Background: B6J.B6NTac(SJL)-Gabrb3^tm1.1Rmac

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

mortality/aging

preweaning lethality, incomplete penetrance ( J:292112 )

• heterozygous females mated with wild-type males produce fewer than the expected number of heterozygous offspring at weaning, indicating increased mortality of heterozygotes

• however, surviving mice have a normal lifespan

behavior/neurological

impaired spatial learning ( J:292112 )

• mice show spatial learning deficits in the Barnes maze that begin early in life (P30-P55) and persist across their lifespan (P180-P220)

• in the Barnes maze, mice take 8 days of learning trials to reach the same level of learning that wild-type mice reach in 5 days

• P30-P55 and P180-P220 mice show a spatial learning deficit in the Barnes maze as measured by the latency to find the target hole and the number of errors committed before entering the target hole

• P30-P55 mice show a less effective search strategy overall and persistently worse search strategy on the final day

abnormal spatial reference memory ( J:292112 )

• mice show spatial memory deficits in the Barnes maze that begin early in life (P30-P55) and persist across their lifespan (P180-P220)

• in the memory trial, P30-P55 mice spend less time investigating the target hole area and make an increased number of errors, indicating a spatial memory deficit in young mice

• P180-P220 mice show a trend towards a decrease in the amount of time spent investigating the target hole area and a significant increase in the number of errors made

decreased aggression towards male mice ( J:292112 )

• adult males do not fight when combined from different cages

increased anxiety-related response ( J:292112 )

• on the elevated zero maze, P180-P220, but not P30-P45, mice spend less time in the open arms of the maze, indicating that young mice exhibit mild anxiety that becomes worse with age

increased thigmotaxis ( J:292112 )

• both P30-P45 and P180-P220 mice travel less through the center of the locomotor activity chambers

decreased social novelty preference ( J:292112 )

• P180-P220, but not P30-P45, mice show loss of preference for novel mouse over a familiar mouse socialization, however mice at both ages show reduced exploratory behavior overall

abnormal righting response ( J:292112 )

• pups show delays in righting when placed on their backs during the neonatal period of P0-P5

hyperactivity ( J:292112 )

• mice exhibit hyperactivity that worsens with age

• P30-P55 mice exhibit a mild hyperactive phenotype with an increased number of vertical counts and a trend towards an increase in total distance travelled

• P180-P220 mice show a more robust hyperactive phenotype, with increase in both vertical counts and total distance traveled

abnormal maternal nurturing ( J:292112 )

♀ • first-time dams fail to nurture their offspring irrespective of pup genotype

♀ • however, nurturing behavior improves for subsequent litters after dams are housed with wild-type foster dams

decreased social investigation ( J:292112 )

• in the three-chamber socialization test, P180-P220 mice have reduced exploratory behavior overall and the preference for novel socialization over a novel object is lost

• however, P30-P45 mice show normal socialization preference

seizures ( J:292112 )

• 4-month-old mice exhibit multiple types of spontaneous seizures

• adult mice most frequently present with atypical absence and myoclonic seizures, while tonic and generalized tonic-clonic seizures are seen much less frequently

• atonic seizures are observed extremely rarely

• all young mice aged P13-P17 show epileptic spasms; spasms are brief, with rapid flexion-extension movements accompanied by behavioral arrest, staring and loss of responsiveness

• more seizures are seen during pregnancy and nursing

• seizure semiologies and ictal EEGs are consistent with a diagnosis of Lennox-Gastaut syndrome

myoclonus ( J:292112 )

• myoclonic seizures are moderately frequent and brief, with sudden muscle contraction involving whole-body extension and flexion associated with a single high-amplitude sharp wave (approximately 200-400 uV) on EEG and EMG channels

tonic seizures ( J:292112 )

• tonic seizures involve a sudden and prolonged contraction of the limbs, with or without tail stiffening, that is associated with either no change in EEG amplitude or low-amplitude, high-frequency activity

• tonic seizures often result in the rolling of the body

tonic-clonic seizures ( J:292112 )

• generalized tonic-clonic seizures are mostly observed in older mice and start with limb stiffening and extension, followed by rapid clonic movements of the limbs, and proceed to strong tonic-clonic activity with abrupt jumps and Straub tail, ending in postictal behavioral arrest

• the ictal EEG shows a high-amplitude, high-frequency discharge followed by a low-amplitude baseline rhythm, followed by a low-activity postictal state lasting up to several minutes

absence seizures ( J:292112 )

• mice exhibit frequent atypical absence seizures characterized by an ictal EEG containing slow spike wave discharges that are poorly formed high-voltage, low-frequency events (3-7 Hz), a longer duration than typical absence, and behavioral arrest and loss of consciousness that are not necessarily tightly time-locked to seizure onset or offset and behavioral arrest that is not always complete

• absence seizures are approximately 97% low-frequency atypical absence seizures compared to wild-type mice which show typical absence seizures

• atypical absence seizures peak at the light-to-dark transition and mice have more atypical absence seizures overall during the dark hours

• treatment with the antiepileptic drugs ethosuximide or clobazam decreases atypical absence seizure duration in the hour after injection of the drug (94% decrease in seizure time for ethosuximide and 73% for clobazam) and ethosuximide, but not clobazam, reduces the number of seizures

• treatment with WIN 55,212-2, a cannabinoid, daily for 7 days reduces by 75% the time spent in atypical absence seizures as well as reduces the number of seizures

• however, topiramate has no effect on reducing atypical absence seizures

growth/size/body

slow postnatal weight gain ( J:292112 )

• pups weigh less than wild-type pups at P21, however they achieve normal body weight by adulthood and no differences are seen in pups in the neonatal (P0-P5) period

integument

delayed skin pigmentation appearance ( J:292112 )

• pups show delays in development of skin pigmentation from P6 to P11

muscle

myoclonus ( J:292112 )

• myoclonic seizures are moderately frequent and brief, with sudden muscle contraction involving whole-body extension and flexion associated with a single high-amplitude sharp wave (approximately 200-400 uV) on EEG and EMG channels

nervous system

nervous system phenotype ( J:292112 )

N • no differences in brain anatomy

seizures ( J:292112 )

• 4-month-old mice exhibit multiple types of spontaneous seizures

• adult mice most frequently present with atypical absence and myoclonic seizures, while tonic and generalized tonic-clonic seizures are seen much less frequently

• atonic seizures are observed extremely rarely

• all young mice aged P13-P17 show epileptic spasms; spasms are brief, with rapid flexion-extension movements accompanied by behavioral arrest, staring and loss of responsiveness

• more seizures are seen during pregnancy and nursing

• seizure semiologies and ictal EEGs are consistent with a diagnosis of Lennox-Gastaut syndrome

myoclonus ( J:292112 )

• myoclonic seizures are moderately frequent and brief, with sudden muscle contraction involving whole-body extension and flexion associated with a single high-amplitude sharp wave (approximately 200-400 uV) on EEG and EMG channels

tonic seizures ( J:292112 )

• tonic seizures involve a sudden and prolonged contraction of the limbs, with or without tail stiffening, that is associated with either no change in EEG amplitude or low-amplitude, high-frequency activity

• tonic seizures often result in the rolling of the body

tonic-clonic seizures ( J:292112 )

• generalized tonic-clonic seizures are mostly observed in older mice and start with limb stiffening and extension, followed by rapid clonic movements of the limbs, and proceed to strong tonic-clonic activity with abrupt jumps and Straub tail, ending in postictal behavioral arrest

• the ictal EEG shows a high-amplitude, high-frequency discharge followed by a low-amplitude baseline rhythm, followed by a low-activity postictal state lasting up to several minutes

absence seizures ( J:292112 )

• mice exhibit frequent atypical absence seizures characterized by an ictal EEG containing slow spike wave discharges that are poorly formed high-voltage, low-frequency events (3-7 Hz), a longer duration than typical absence, and behavioral arrest and loss of consciousness that are not necessarily tightly time-locked to seizure onset or offset and behavioral arrest that is not always complete

• absence seizures are approximately 97% low-frequency atypical absence seizures compared to wild-type mice which show typical absence seizures

• atypical absence seizures peak at the light-to-dark transition and mice have more atypical absence seizures overall during the dark hours

• treatment with the antiepileptic drugs ethosuximide or clobazam decreases atypical absence seizure duration in the hour after injection of the drug (94% decrease in seizure time for ethosuximide and 73% for clobazam) and ethosuximide, but not clobazam, reduces the number of seizures

• treatment with WIN 55,212-2, a cannabinoid, daily for 7 days reduces by 75% the time spent in atypical absence seizures as well as reduces the number of seizures

• however, topiramate has no effect on reducing atypical absence seizures

abnormal ictal brain wave pattern ( J:292112 )

• mice exhibit frequent atypical absence seizures characterized by an ictal EEG containing slow spike wave discharges that are poorly formed high-voltage, low-frequency events (3-7 Hz)

• the ictal EEG of generalized tonic-clonic seizures shows a high-amplitude, high-frequency discharge followed by a low-amplitude baseline rhythm, followed by a low-activity postictal state lasting up to several minutes

• myoclonic seizures show a single high-amplitude sharp wave (approximately 200-400 uV) on EEG and EMG channels

• tonic seizures are associated with either no change in EEG amplitude or low-amplitude, high-frequency activity

abnormal CNS synaptic transmission ( J:292112 )

• spontaneous thalamocortical network oscillations of thalamic ventrobasal nucleus neurons are longer and more frequent

abnormal miniature inhibitory postsynaptic currents ( J:292112 )

• mIPSC charge transfer is decreased in pyramidal neurons

decreased miniature inhibitory postsynaptic current amplitude ( J:292112 )

• somatosensory cortex layer V/VI pyramidal neurons exhibit decreased GABAA receptor-mediated mIPSC amplitude

prolonged miniature inhibitory postsynaptic current decay phase ( J:292112 )

• somatosensory cortex layer V/VI pyramidal neurons exhibit increased mIPSC decay time constant, with no change in mIPSC frequency

pigmentation

delayed skin pigmentation appearance ( J:292112 )

• pups show delays in development of skin pigmentation from P6 to P11

reproductive system

reduced male fertility ( J:292112 )

♂

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Lennox-Gastaut syndrome		DOID:0050561	OMIM:606369	J:292112