Possible Interaction between KCNA1 Genotype and Aging on Auditory Spatial Discrimination in the Mouse Paul D. Allen, Peter J. Rivoli, James R. Ison Department of Brain & Cognitive Sciences, University of Rochester, Rochester, NY ARO Introduction Methods KCNA1 +/- mice do not appear to show poorer spatial discrimination than their +/+ littermates In fact, the effect of aging on spatial acuity may be stronger in the +/+ than +/- mice, but is still less pronounced than previously observed in the CBA/CaJ mouse Subjects: C3HeB/FeJ-Kcna1 tm1Tem mice 4-8 months (18 +/-, 13 +/+) 9-16 months (28 +/-, 24 +/+) months (19 +/-, 22 +/+) months (5 +/-, 5 +/+) Mice held in acoustically transparent wire cage mounted to a platform and accelerometer Startle eliciting stimulus (ES) delivered overhead (120dB SPL, 15 ms broadband noise burst) Startle response recorded from accelerometer (RMS 100ms window, post-ES) Spectrally-matched high-frequency speakers (TDT ES1) located 45cm from the mouse head Angular separations: 180, 90, 45, 22.5, or 7° Cage oriented with head facing mid-line of the two speakers Continuous broadband noise (60 dB SPL, 1-50kHz) presented from one speaker (min 15s, ave 20s) Prepulse is noise-swap between speakers at set inter-stimulus interval (ISI) prior to ES ISI conditions: 1, 2, 5, 10, 20, 30, 40, 50, 60, 100, 150, 200, 300 ms, two no-prepulse controls, and a no-startle, no-swap activity control Speaker angle is fixed in each session (counterbalanced design) with 11 presentations of each condition, block randomized Inhibition calculated relative to no-prepulse controls (responses to1 st presentations excluded) Low-threshold K+ conductances underpin temporal processing and control synchrony in neurons of the auditory brainstem. The Kv1.1 channel is strongly expressed in the MNTB, a nucleus involved in ILD processing. We have previously demonstrated that mice lacking the KCNA1 gene, which codes for the Kv1.1 channel, have deficits in auditory spatial discrimination using a novel behavioral task based on pre-pulse inhibition of startle. We have also shown that the same behavioral task reveals progressive degradation of auditory spatial discrimination from 3 to 24 months of age in the CBA/CaJ mouse. In the current study we test the hypothesis that there is an interaction between genotype and age in KCNA1 +/+ and +/- mice in auditory spatial discrimination, specifically that the heterozygote mice, with only one copy of the gene, will show stronger age related declines than their wild-type littermates. Supported by NIA Grant #AG09524 and The Schmitt Program on Integrative Brain Research +/+ +/-  (+/-,+/+) 4-8 mo 9-16 mo mo mo 180° and 45° for each genotype vs. age 90° for each Age: Genotypes and their differences Auditory Spatial Discrimination does not appear to be poorer in KCNA1 +/- than +/+ mice with increasing age Interpretive Rule of Thumb: Rd’( difference from control ) > 0.6 corresponds to ~P < 0.05 i.e. On 3-D surface plots on the left, orange and red show regions that are on average, for each individual, significantly inhibited by the change in spatial location For a given ISI, Rd’ scales with angle and is reduced in old age We showed previously that KCNA1 -/- mice have a deficit in auditory spatial acuity Increased jitter of onset latencies in the MNTB (Kopp-Scheinpflug et al, 2003) may disrupt ILD sensitivity in the LSO e.g. via corruption of the time-intensity trading mechanism No deficit found here in KCNA1 +/- mice, even though they have only half as much Kv1.1 as the +/+ Could compensation in the +/- impart resistance to the aging-related decline of spatial acuity? These data indicate that a single copy of the KCNA1 gene is sufficient for normal spatial acuity well into old age, but direct measurements of K+ channel expression as a function of age are required in order to determine the molecular mechanisms underpinning this process. C3H mice may live longer than CBA mice, and have only mild hearing loss (~20 dB) at 26 months of age No differences in ABR thresholds across genotype These mice have good and very similar temporal acuity as measured with behavioral and electrophysiological gap detection (Allen et al., and Ison et al., ARO 2002) SAM encoding in the CN shows some differences between young KCNA1 +/+ and +/-, but not in the IC (Schmuck et al. # 900 at this meeting) ISI = 50 ms