behavior/neurological phenotype

• increased susceptibility to pharmacologically induced seizures
  • administration of 50 mg/kg pentylenetetrazol, induces generalized convulsions (with loss of posture, myclonic jerks, hyperextension of neck and trunk associated with cycling motions of limbs and extension of hind limbs) in wild-type and mutant mice with similar frequency, but slightly shorter latency in mutants; >50% of mutants die within minutes of end of tonic-clonic phase of seizures, whereas no wild-type animals die
  (MGI Ref ID J:38857)
  • imilar frequency, but slightly shorter latency in mutants; >50% of mutants die within minutes of end of tonic-clonic phase of seizures, whereas no wild-type animals die
  (MGI Ref ID J:38857)

• seizures
  • over long-term observation, seizures are observed
  (MGI Ref ID J:38857)

mortality/aging

• premature death
  • ~15% of homozygotes die by ~4 months, starting at about 3 weeks of age
  (MGI Ref ID J:38857)

nervous system phenotype

• abnormal cerebral cortex morphology
  • mutant cortex contains aberrant fascicles in the neocortex and no fascicles are seen in the lateral-ventral portion of the cortex
  (MGI Ref ID J:38857)
  • laminated structure is not apparent in 3-month old mice; defects in lamination are less severe in lateral-ventral region of cortex
  (MGI Ref ID J:38857)
  • cortex shows mild neuronal-positioning abnormalities
  (MGI Ref ID J:71181)
  • no recognizable pattern is observed for distribution of pyramidal, granule, and polymorphic cells in cortex
  (MGI Ref ID J:38857)
  • radial distribution of pyramidal neurons and their apical dendrites is not conspicuous like in wild-type brains
  (MGI Ref ID J:38857)

• abnormal hippocampus morphology
  (MGI Ref ID J:38857)
  • at E18.5, hippocampus shows signs of disorganization, but this is less severe than in double null mutants
  (MGI Ref ID J:71181)

• thin cortical plate
  • cortical plate is 30-50% thinner than in wild-type embryos at E15
  (MGI Ref ID J:38857)

• abnormal olfactory bulb development
  • internal plexiform layer between mitral cell layer and internal granule layers is absent
  (MGI Ref ID J:38857)

• increased susceptibility to pharmacologically induced seizures
  • imilar frequency, but slightly shorter latency in mutants; >50% of mutants die within minutes of end of tonic-clonic phase of seizures, whereas no wild-type animals die
  (MGI Ref ID J:38857)
  • administration of 50 mg/kg pentylenetetrazol, induces generalized convulsions (with loss of posture, myclonic jerks, hyperextension of neck and trunk associated with cycling motions of limbs and extension of hind limbs) in wild-type and mutant mice with similar frequency, but slightly shorter latency in mutants; >50% of mutants die within minutes of end of tonic-clonic phase of seizures, whereas no wild-type animals die
  (MGI Ref ID J:38857)

• abnormal cerebral cortex pyramidal cell morphology
  • orientation of neuronal soma and direction of dendritic growth are altered; defect is more severe in medial neocortex
  (MGI Ref ID J:38857)

• decreased corpus callosum size
  • size (thickness) is significantly reduced
  (MGI Ref ID J:38857)

• decreased striatum size
  • size is reduced
  (MGI Ref ID J:38857)

• abnormal hippocampus layer morphology
  • layers II and III are occupied by large instead of small pyramidal neurons
  (MGI Ref ID J:38857)
  • most cells in hippocampus and dentate gyrus are included in a laminar structure like in wild-type, but cells are less densely packed
  (MGI Ref ID J:38857)

• abnormal subplate morphology
  • at E18.5, an ectopic cortical subplate is detected under the most superficial cortical plate with later-born cortical neurons accumulated underneath
  (MGI Ref ID J:71181)

• dilated lateral ventricles
  • lateral ventricles are ~twice the size of lateral ventricles in wild-type brain in 3-month old animals
  (MGI Ref ID J:38857)

• abnormal cerebellar molecular layer
  • molecular layer shows a greater cell density than wild-type, and contains cells resembling granule cells
  (MGI Ref ID J:38857)

• abnormal forebrain morphology
  • in three-month old mice, general disorganization of forebrain is apparent
  (MGI Ref ID J:38857)

• seizures
  • over long-term observation, seizures are observed
  (MGI Ref ID J:38857)

• abnormal dentate gyrus morphology
  (MGI Ref ID J:38857)

• ectopic Purkinje cell
  • some cells are located in granule cell layer
  (MGI Ref ID J:38857)

behavior/neurological phenotype

• abnormal behavioral response to xenobiotic
  • mice dosed repeatedly with psychostimulants exhibit hypolocomotion, such that by the 5th day of methylphenidate (MPH) dosing, locomotor activity is reduced to 63% of controls
  (MGI Ref ID J:204269)
  • mice exhibit a hypolocomotive response to repeated injections of cocaine
  (MGI Ref ID J:204269)

• seizures
  (MGI Ref ID J:38857)

• hyperactivity
  • mice show hyperactivity over a 60-minute testing period compared with controls
  (MGI Ref ID J:204269)

• abnormal sensitization to xenobiotic
  • mice are deficient in sensitization to repeated injections of cocaine
  (MGI Ref ID J:204269)
  • mice do not exhibit sensitized responses to MPH dosing over 5 days as seen in wild-type mice
  (MGI Ref ID J:204269)

homeostasis/metabolism phenotype

• abnormal physiological response to xenobiotic
  • dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), levels are reduced in the striatum and prefrontal cortex of mice dosed with MPH for 5 days, however basal levels of both are normal
  (MGI Ref ID J:204269)
  • after chronic MPH treatment, mice show about a 51% reduction in dopamine turnover compared to chronically treated wild-type mice
  (MGI Ref ID J:204269)
  • chronic MPH induces a 1.08-fold increase in 5-HT, an 18% decrease in 5-HIAA, and a 23% decrease in 5-HT turnover in mutants compared to wild-type mice
  (MGI Ref ID J:204269)
  • dopamine turnover is increased in response to repeated MPH treatment compared to un-treated mutants while treatment of wild-type mice with MPH has no effect on dopamine turnover
  (MGI Ref ID J:204269)
  • Normal - no differences are seen in the caudate putamen after MPH treatment
  (MGI Ref ID J:204269)

• increased serotonin level
  • mice exhibit small, but significant, elevations in basal serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels
  (MGI Ref ID J:204269)

mortality/aging

• premature death
  (MGI Ref ID J:38857)

nervous system phenotype

• abnormal cerebral cortex morphology
  (MGI Ref ID J:38857)

• abnormal hippocampus morphology
  (MGI Ref ID J:38857)

• abnormal striatum morphology
  (MGI Ref ID J:38857)

• decreased corpus callosum size
  (MGI Ref ID J:38857)
  • size of the corpus callosum is severely reduced
  (MGI Ref ID J:204269)

• abnormal hippocampus layer morphology
  (MGI Ref ID J:38857)

• increased serotonin level
  • mice exhibit small, but significant, elevations in basal serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels
  (MGI Ref ID J:204269)

• seizures
  (MGI Ref ID J:38857)

• ectopic Purkinje cell
  (MGI Ref ID J:38857)

• abnormal axon extension
  • neurons fail to respond to BDNF treatment with increased spine density unlike wild-type cells
  (MGI Ref ID J:193542)

• abnormal forebrain development
  (MGI Ref ID J:38857)

• abnormal forebrain morphology
  • mice on 129 inbred background show the phenotypes observed on the mixed 129Sv/C57BL/6 background
  (MGI Ref ID J:38857)

• abnormal stratification in cerebral cortex
  • lamination of the cerebral cortex is abnormal
  (MGI Ref ID J:204269)

• abnormal dentate gyrus morphology
  (MGI Ref ID J:38857)

• abnormal olfactory bulb development
  (MGI Ref ID J:38857)

• abnormal innervation
  • mice show an increased density of dopaminergic fiber innervation in the infralimbic, prelimbic, and cingulate cortices
  (MGI Ref ID J:204269)
  • tracer analysis indicates that mutants exhibit a loss in the layer-specific afferentiation of descending medial prefrontal cortex outputs projecting to the nucleus accumbens
  (MGI Ref ID J:204269)

• abnormal cerebellar molecular layer
  (MGI Ref ID J:38857)

• dilated lateral ventricles
  (MGI Ref ID J:38857)

• reduced long term potentiation
  • following application of BDNF
  (MGI Ref ID J:193542)

cellular phenotype

• abnormal axon extension
  • neurons fail to respond to BDNF treatment with increased spine density unlike wild-type cells
  (MGI Ref ID J:193542)

• increased cellular glucose import
  • mice show a greater rate of glucose uptake in the cerebral cortex
  (MGI Ref ID J:204269)