Analysis Tools
behavior/neurological
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• mutant mice do not show any defects in motor coordination in the rotarod
task compared to controls
• no apparent decrease in locomotion or locomotor activity is seen in mutant mice compared to controls
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• mutant mice show reduced ethanol preference compared to controls
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• mutant mice drink less ethanol than control littermates
• consumption of bitter (quinine) or sweet (saccharin) solutions did not differ between mutant and control mice
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• mutant mice placed on an accelerating rotarod after injection of 2 gm/kg ethanol showed a shorter latency to fall compared with control mice; lower doses of ethanol did not produce this effect; a significant difference in latency to fall between mutant and control mice is also seen at 15 and 30 min after injection
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• mice lose their righting reflex for a significantly shorter duration compared to controls at the same ethanol dosage
• the threshold dose of ethanol required to produce a loss of the righting reflex is significantly higher in mutant mice than in controls
• Background Sensitivity: these phenotypes are also seen when mice are studied on an coisogenic 129S4/SvJae genetic background
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• in a conditioned taste aversion assay with ethanol as the unconditioned stimulus and 1.2% NaCl as the conditioned stimulus, both control and mutant mice rapidly develop conditioned taste aversion; however, the magnitude of conditioned taste aversion is significantly reduced in mutant mice compared with controls
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• control mice trained with 2 gm/kg ethanol showed robust ethanol-induced place conditioning for ethanol while this response was completely absent in mutant mice; however, mutant mice did develop place preference at a lower dose of ethanol (1.2 gm/kg) that did not produce place preference in control mice
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• 24 hours after interaction with demonstrator mice, mutant mice do not show a preference for the food cued by the demonstrator mice, whereas control mice show a strong preference for the cued food
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• although the time taken to find a hidden platform in a Morris water maze decreased with training, mutant mice exhibit significantly longer escape latencies throughout the training period than do control mice
• a visible platform test using nae mice shows that no differences in escape latency is seen between mutant and control mice, indicating that sensorimotor system function, motivation and emotional status does not affect performance of mutant mice in the Morris water maze test
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• in probe trials after three and seven training blocks in the Morris water maze, mutant mice do not show a preference for the target quadrant, whereas control mice spend more time searching there and cross the hidden platform more frequently
• in probe trials after twelve training blocks in the Morris water maze, mutant mice can improve performance to similar control levels
• in probe trials after twelve training blocks, then a two week rest period and then two additional training blocks, mutant mice lose the ability to recall the target platform location, assessed by time spent in the target quadrant, unlike controls
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• in a resident- intruder test, mutant mice exhibit a shortened latency to the first attack on an intruder mouse, and an increased number of attacks compared to controls
• in a duration of water consumption test, mutant male mice display a longer duration than controls, suggesting a dominant social behavior when housed together with controls; no difference is seen when mutant and control mice are housed separately
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• response scores for a broad range of mechanical stimuli in paw withdrawal and tail flick tests are reduced in mutant mice
• thresholds of both paw withdrawal and tail flick are shifted to higher intensity on the response-intensity curve, showing that N-type calcium channels are necessary for acute nociception
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• the biphasic pain response of mutant mice exhibit significantly attenuated response in Phase 2, but normal pain behaviors in Phase 1 when hindpaws are injected with 2% formalin
• the stretching/writhing motion response to visceral inflammatory pain caused by injection of 0.6% acetic acid into the peritoneal cavity is reduced in mutant mice
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• mutant mice exhibit longer latencies to paw withdrawal and tail flick in the radiant heat assay compared to controls
• however, pain behavior (licking, biting, or flicking) to noxious heat stimuli in the hot plate test was the same for mutant and control mice
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nervous system
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• gross morphologies of the mutant dorsal root ganglia and brain is similar to control mice
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• the levels of 5-HT and 5-HIAA were significantly elevated in the mutant hypothalamus compared with those of the controls, indicating increased 5-HT release in the mutant hypothalamus
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• action potential shapes measured by whole cell patch clamp recordings of 5-HT neurons in the DRN indicate that no differences is seen in the amplitude or duration of action potential or in the amplitude of after hyperpolarization between mutant and control neurons; however, when the membrane potential is depolarized by intracellular current injection, these neurons fire more frequently in the mutant mice than in the controls
• application of bicuculline, a GABAA receptor antagonist to 5-HT neurons in the DRN increases the firing rates in both mutant and control mice, but a significant increase remains in the magnitude of the firing rate in mutant compared to control mice
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• in slices derived from mutant mice, 5-HT neurons in the dorsal raphe nucleus (DRN) induced by phenylephrine fire more frequently in culture than controls
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• fEPSPs were recorded from area CA1 of the hippocampus in response to the stimulation of Schaffer collateral fiber; in mutant mice, the input-output relation of synaptic transmission was reduced; this value is equivalent to control mice that are treated with omega-GVIA, an N-type VDCC blocker
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• after a focal stimulation within the DRN, the maximum amplitude of eIPSC in the mutant neurons was lower than that in the control; in addition, application of omega-GVIA to the control slice significantly reduced the amplitude of eIPSC
• there was no difference in the frequency or amplitude of the spontaneous excitatory postsynaptic current (mEPSC) between mutant and control neurons, and the maximum amplitude of evoked excitatory postsynaptic current (eEPSC) in the mutant mice was also similar to that of the control
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• long-term potentiation induced by 200-Hz tetanic stimulation and theta burst stimulation (TBS) on hippocampal synapses is significantly reduced in mutant mice and is equivalent to the value in control mice treated with omega-GVIA, an N-type VDCC blocker; no difference is seen using 50-Hz tetanic stimulation
• application of BDNF to hippocampal slices enhances the synaptic transmission capabilities in both mutant and control mice, but a significant reduction remains in the amplitude of BDNF-mediated potentiation in mutant compared to control mice
• long term depression is not altered in mutant mice
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• in CA1 pyramidal neurons, mutant mice show mEPSC frequencies similar to controls; upon application of BDNF, both mutant and control mice exhibit an increase in frequency of mEPSCs in these neurons, but the increase in mutant mice is significantly lower than in controls
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• the frequency of sIPSC in mutant neurons was significantly reduced compared with that of control neurons without any significant change in the amplitude; this reduction of sIPSC in the mutant neurons was mimicked in the control slices by an N-type channel
blocker (omega-GVIA)
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• in small-diameter dorsal root ganglion (DRG) neurons from mutant mice, the profile of calcium channel currents supported by Ba2+ as the charge carrier was characterized by successive applications of specific blockers; IBa in mutant mice was inhibited by the L-type calcium channel blocker (nifedifine), but not by the N-type calcium channel blocker (v-conotoxin- GVIA), showing a specific reduction in density of the N-type calcium channels
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homeostasis/metabolism
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• no difference is noted between mutant mice and controls in the clearance of ethanol from the blood after injection of 4 gm/kg ethanol, showing that mutant mice do not exhibit altered ethanol metabolism
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