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PATTERNS OF NORMAL AND ABNORMAL AUDITORY BEHAVIOR IN POTASSIUM CHANNEL KNOCK OUT MICE.

PATTERNS OF NORMAL AND ABNORMAL AUDITORY BEHAVIOR IN POTASSIUM CHANNEL KNOCK OUT MICE. J.R. Ison* 1 , P.D. Allen 1 , M. Zettel 1 , R.H. Joho 2 1. Brain & Cognitive Sciences, Univ. of Rochester, Rochester, NY, USA. 2. Ctr. for Basic Neurosci, U.T. Southwestern Med. Ctr., Dallas, TX, USA.

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PATTERNS OF NORMAL AND ABNORMAL AUDITORY BEHAVIOR IN POTASSIUM CHANNEL KNOCK OUT MICE.

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  1. PATTERNS OF NORMAL AND ABNORMAL AUDITORY BEHAVIOR IN POTASSIUM CHANNEL KNOCK OUT MICE. J.R. Ison*1, P.D. Allen1, M. Zettel1, R.H. Joho2 1. Brain & Cognitive Sciences, Univ. of Rochester, Rochester, NY, USA. 2. Ctr. for Basic Neurosci, U.T. Southwestern Med. Ctr., Dallas, TX, USA SFN 2004 987.15 Introduction Slice preparations in vitro and electrophysiology in vivousing specific neurotoxins and/or KO mice to eliminate K+ channels confirms their role in maintainng temporal precision and high firing rates in CN and MNTB (Macica et al., JNeurosci. 2003; Kopp-Scheinpflug et al. JNeurosci. 2003). Other evidence reveals age-related decrements in Kv channel expression in the auditory brainstem of old mice (Zettel & Frisina, ARO 2004). It is interesting that the auditory abilities apparently dependent on Kv channels are those in which aged listeners are deficient, in, e.g., the inability to follow acoustic transients. To further this attempt to understand the physiological bases of presbycusis, as well as to extend the physiological findings to the behaving animal, we have begun to characterize the functional significance of the Shaker and Shaw Kv channels by studying auditory behaviors in potassium channel KO mice: here we report initial findings for Kv3.1 KO mice that provide a suggestive deficit in one type of auditory behavior, but not others. The genetic background of the mice used for this research was an unusual 129Sv-C57BL/6-ICR outbred hybrid (usually )albino strain. Some curious aspects of our findings suggest that the effect of maturation on all of these mice, wild type and knock-out, is intrinsically interesting in its own right, in showing an effect on suprathreshold but not threshold auditory processing. Results 3: Startle responsesHo et al. (1999) found small differences favoring +/+ compared to -/- Kv3.1 KO mice in the ASR to tone bursts. Fig. 3 shows the ASR to white noise bursts in each mouse in the litters that had all 3 genotypes present. No genotype effects are apparent in the comparisons across genotypes (from -/- on the left to +/+ on the right). Conclusions:These results (1 to 5) suggest that the auditory behavior of the Kv3.1 null mutant differs little from that of the wild type mouse. There are no striking differences in weight or in ABR thresholds, no differences in the ASR to white noise bursts presented at different levels, no differences in the inhibitory effect of SAM stimulation, and only a modest deficit in the inhibitory effect of switching the location of a sound object by 90 degrees (this tentative finding is not yet certain and requires further work). In contrast the Kv1.1 -/- mouse weighs less than the +/+, has a hyperexcitable asynchronous ABR, and while also showing no SAM effect, has a profound deficit in detecting shifts in sound localization. Young adult Kv1.1 -/- mice have seizures and die, while Kv3.1 -/- mice do not have seizures. Porcello et al. (2002) found in vitro that neurons in a Kv3.1 -/- slice from the reticular thalamic nucleus retained fast firing rates, thissuggesting redundancy amongst the Kv3 family: compensatory changes in other Kv3 channels might account for the modest behavioral deficits in the Kv3.1 -/- mouse. Peculiar ASR and ABR finding in this outbred strain:All of the prior data were obtained in mice from 24 to 32 days old. We tested the ASR and the ABR again at 5 to 6 months of age (so far just the first 2 litters, 2 -/-, 4 +/+, and 10 +/-) with the following results: Results 1: Body Weights Ho et al. (PNAS 1997) found that Kv3.1 NM (-/-, n =8) mice on a pure 129Sv background weighed less than +/- (n = 22) littermates. Fig 1 shows the weights at 24-26 days of age of +/+, +/- and -/- mice in 3 litters that had all three genotypes present. There was substantial overlap across genotypes but litters were very different. Results 4: Inhibition by SAM stimuli.Macica et al. (2003) found that cells in MNTB slices from 14 day old Kv3.1 -/- mice failed to respond to 300 Hz current injections, in contrast to WT. We used 100% mod. SAM of 70 dB SPL noise to inhibit the ASR. Inhibition did not vary with Kv3.1 genotype, which is similar to our Kv1.1 data in showing equal detection of SAM. Fig. 6: Reduced ASR in all 7 mice of Litter 1; ASR went down in 3 but up in 4 mice in Litter 2 and 2 remained the same (Note the large SEM) Fig. 7: There was no change in thresholds (A) but a large loss in ABR RMS in all mice with increased age (B) . Results 2: ABRAdamson et al. (JCN, 2002) found that basal spiral ganglion cells expressed more Kv3.1 and 1.1 subunits than did apical cells, suggesting specializaton for coding high frequency inputs that might affect ABR thresholds (mean, SEM on left). Kv1.1 KO mice have higher asynchronous ABR activity than WT (Ison, SFN 2002). The suggestive 48 kHz difference seen in Figure 2A is not significant, and there is no obvious difference between mice in RMS (total power in the wave form) in Fig. 2B (data shown for 16 kHz, 90 dB) Results 5: Inhibition by changing sound locationAllen et al. (SFN 2003) found a profound deficit in ASR inhibition to switching a noise from one location to another in the Kv1.1 -/- mouse. Here a 90 degree shift across the midline was presented at different intervals before the ASR. There is a suggestive but relatively small deficit in the Kv3.1 -/- KO mice. Implications:The data shown in Figures 6 and 7 show a surprising disjunction between the absence of an age effect on ABR thresholds and a major effect on the suprathreshold ABR and the ASR in these hybrid mice, which occurred in all genotypes. It may be an auditory anomaly peculiar to this particular hybrid combination. However, it may be more common amongst different mouse strains, but has simply not been made evident in the research that has studied ASR differences across strains (Paylor & Crawley, 1997, e.g.). The data show the importance of assessing auditory function by suprathreshold as well as the threshold ABR. The locus of the ASR and ABR effects seen in Figures 6 and 7B must be in the cochlea rather than the brain because of the absence of a robust P1 in the suprathreshold ABR. It cannot be in the OHC because of apparently normal thresholds seen in Figure 7A. We suggest testing the hypothesis that the suprathreshold effects result from a partial loss of IHC that is more or less evenly distributed across the basilar membrane. Research supported by AG09524, by DC05409, and by the Schmitt Program on Integrative Brain Research

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