Impaired Subcortical Processing of Amplitude-Modulated Tones in Mice Deficient for Cacna2d3, a Risk Gene for Autism Spectrum Disorders in Humans

Examples of neuronal responses to AM tone stimulation of α₂δ3^+/+ and α₂δ3^−/− mice. A, Raster plot from an α₂δ3^+/+ unit responding with action potentials (dots) to AM tone stimulation of modulation frequencies between 0 and 100 Hz showing an onset response and subsequent phase locking over the entire range of AMs (significant vector strength, Rayleigh test, p = 0.01). B, Raster plot from an α₂δ3^−/− unit showing a similar response with phase-locking up to 70-Hz modulation frequency (significant vector strength, Rayleigh test, p = 0.01). In both examples, the carrier frequency was set to the BF of the unit, here 11,310 Hz. Responses to each modulation frequency are represented by 15 horizontal rows of dots corresponding to 15 trials. The green area indicates the duration of the stimulus.

IC units of α₂δ3^−/− mice lose precision of temporal coding and show a reduced evoked rate to higher modulation frequencies. A–C, Evoked rate (activity averaged over all AM tone stimulations at a particular modulation frequency) for all units with carrier frequency of the AM tone equal to their BF of α₂δ3^+/+ (+/+, black, n = 97) and α₂δ3^−/− (−/−, red, n = 99) mice as a function of time. Averaged evoked rate (PSTH) is shown for f_m = 10 Hz (A), f_m = 30 Hz (B), and f_m = 100 Hz (C). The AM stimulus with 500-ms duration is shown above each panel. This figure was created using a binning time of 1 ms.

AM tone-evoked rates of the population were lower in α₂δ3^−/− mice compared with α₂δ3^+/+; the difference of evoked rates between genotypes increased on high modulation frequencies. A–F, AM tone-evoked rates of IC units from α₂δ3^+/+ (+/+, black, n = 97 for f_m ≤ 100 Hz; n = 77 for f_m > 100 Hz) and α₂δ3^−/− (−/−, red, n = 99 for f_m ≤ 100 Hz; n = 73 for f_m > 100 Hz) mice as a function of the period of the respective f_m and for selected modulation frequencies. The onset response is visible in the first periods of each modulation frequency.

Median FSLs were longer in IC units of α₂δ3^−/− compared with α₂δ3^+/+ mice at some modulation frequencies. FSLs (A) and FSLs in relation to the periodic time (B) of neuronal responses to AM tone stimulation of α₂δ3^+/+ units (+/+, black) and α₂δ3^−/− units (−/−, red) as a function of modulation frequency. Box plots with medians (horizontal lines), interquartile ranges (25% and 75%, boxes) and whiskers (10%, 90%) of FSL. FSL of the neuronal response to the unmodulated carrier frequency (0 Hz, PT, left, filled box plot) and to different modulation frequencies (10–160 Hz) for α₂δ3^+/+ (n = 97 for f_m ≤ 100 Hz; n = 77 for f_m > 100 Hz) and α₂δ3^−/− units (n = 99 for f_m ≤ 100 Hz; n = 73 for f_m > 100 Hz; Mann–Whitney U test, *p < 0.05).

Peak latencies of IC units from α₂δ3^−/− mice are longer compared with those from α₂δ3^+/+ mice. Population peak latency ± SD (jitter; A) and population peak latency ± SD (jitter; B) in relation to the periodic time of neuronal responses to AM tone stimulation for units of α₂δ3^+/+ (+/+, black) and α₂δ3^−/− mice (−/−, red). C, Mean peak latency ± SD calculated from each of neuronal responses to AM tone stimulation and each period. D, Mean peak latency ± SD in relation to periodic time of AM tone stimulation. *p < 0.05; **p < 0.01; ***p < 0.001.

Peak latencies of the population of IC units remain largely constant as a function of period in both α₂δ3^+/+ and α₂δ3^−/− mice. A–F, Peak latencies of the population of α₂δ3^+/+ (+/+, black) and α₂δ3^−/− units (−/−, red) for selected modulation frequencies are constant over the period of AM tone stimulation for both genotypes except some jitter in panels D–F.

Unexpected dependence of the vector strength of the population on the modulation frequency for IC units from α₂δ3^−/− mice. For modulation frequencies below ∼60 Hz, population vector strength was higher for α₂δ3^−/− units (−/−, red) compared with α₂δ3^+/+ units (+/+, black). For f_m ∼80 Hz and above, population vector strength of α₂δ3^−/− units declined below that of α₂δ3^+/+ units.