Analysis Tools
behavior/neurological
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• at 8-11 weeks of age, homozygotes show normal sensorimotor reflexes, including whisker touch, ear twitch, and eye blink, relative to wild-type controls
• neuromuscular strength (wire hang test), pain sensitivity (tail flick test), and motor performance/coordination (rotarod test) are normal
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• after i.p. injection of methylphenidate (0.3, 3.0 or 10 mg/kg), homozygotes exhibit significantly higher horizontal locomotor activity than wild-type controls in the open field test
• maximum level of horizontal activity is achieved at a dose of 3 mg/kg in mutant mice versus 10 mg/kg in wild-type mice
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• at 8-11 weeks of age, homozygotes show slightly increased daily food intake relative to wild-type controls
• daily food intake is significantly increased after adjusting for body weight
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• homozygotes show reduced depression-like behavior in the tail suspension and forced swim tests, with significantly decreased immobility time observed in both tests
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• in the elevated plus maze test, homozygotes spend more time in the open arms and show an increased number of entries into the open arms relative to wild-type controls
• in the light/dark transition test, the number of transitions between light and dark is significantly higher than in wild-type controls
• homozygotes produce fewer fecal boli than wild-type mice during the open-field, elevated plus maze, and light/dark transition tests
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• homozygotes show an increased acoustic startle response to a 100 dB acoustic stimulus
• however, prepulse inhibition (PPI) is not significantly altered
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• at 8-11 weeks of age, homozygotes show pronounced hyperactivity in multiple behavioral tests
• homozygotes spend less time immobile in both novel and familiar environments
• in the contextual and auditory fear conditioning tests, homozygotes show reduced levels of freezing after shock and also during cued testing, likely due to hyperactivity
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• in the open-field test, homozygotes show increased vertical activity in a novel environment
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• horizontal activity is increased in both novel and familiar environments
• in the open-field test, overall locomotor activity in a novel environment is increased, as shown by increased distance traveled, an increased number of vertical activities, and reduced immobility time relative to wild-type controls
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• reduced fertility between male and female homozygotes is likely due to abnormalities in social or sexual behavior
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growth/size/body
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• at 8-11 weeks of age, homozygotes weigh ~10% less than wild-type controls
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homeostasis/metabolism
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• homozygotes show a significantly higher dopamine turnover ratio ([3,4-dihydroxyphenylacetic acid (DOPAC) + homovanillic acid (HVA) + 3-methoxytyramine (3-MT)]/dopamine) in the striatum relative to wild-type controls
• striatal levels of DOPAC, HVA, and 3-MT are increased, whereas dopamine levels remain unchanged
• striatal levels of norepinephrine, 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) and the serotonin turnover ratio (5-HIAA/5-HT) are normal
• no alterations are observed in levels of norepinephrine, dopamine, DOPAC, HVA, 5-HT, or 5-HIAA in the prefrontal cortex or hippocampus
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nervous system
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• in culture, mutant cortical neurons appear morphologically normal with no detectable differences in neurite length or the shape and number of spines
• basal synaptic efficacy is normal, as shown by normal ratio of NMDAR-mediated EPSC amplitudes to AMPAR-mediated EPSC amplitudes, normal AMPAR-mediated synaptic responses, and normal NMDA current kinetics in mutant hippocampal slices
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• in culture, mutant cortical neurons exhibit impaired endocytic trafficking of the N-methyl-D-aspartate (NMDA) receptor
• although intracellular levels of the GluN1 and GluN2B subunits of the NMDA receptor are significantly increased, total or surface levels of NMDA receptors appear relatively unaffected
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reproductive system
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• male homozygotes exhibit grossly normal testis histology with no detectable alterations in caudal epididymal sperm morphology and motility
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• both male and female homozygotes appear to be fertile, although female homozygotes rarely become pregnant after mating with male homozygotes
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