Extended Data Figure 1. 5XFAD mice have reduced power in gamma during hippocampal SWRs
b) Mouse in virtual reality environment. c) Local field potential recorded in CA1, above, filtered for theta
(left) or sharp wave ripples (right), middle, and gamma, below. d) Mean and standard deviation of the normalized power spectrum
during theta. Each animal's power spectral density was normalized to
its peak (n=6 mice per group). e) Normalized power spectral densities during theta periods in
3-month-old 5XFAD (green, n=6 mice) and WT (black/grey, n=6
mice) mice. Each animal's power spectral density was normalized to
its peak (in theta). f) Average SWR-triggered spectrograms for one WT and one 5XFAD mouse
shows an increase in the gamma band during SWRs. This increase is lower in
the 5XFAD mouse than in the WT mouse (n=370 and 514 SWRs in WT and
5XFAD, respectively; WT mouse shown here is the same as in Fig. 1a). g) Distributions for each recording (left) and the mean and standard
error across sessions (right) of instantaneous gamma frequencies during SWRs
in 5XFAD (green) and WT (black) mice show distributions around 40 Hz
(n=820, 800, 679, 38, 1875, 57 gamma cycles per session in 6 5XFAD
animals and 181, 1075, 919, 1622, 51, 1860, 1903 gamma cycles per session in
6 WT animals). h) Cumulative distribution of the Z-scored gamma power during the
100 ms around the peak of the SWR for WT (black) and 5XFAD animals (green)
for each animal (left) and the mean and standard error (shaded) across
animals (right) (n=514, 358, 430, 22, 805, 37 SWRs per session in 6
5XFAD animals and 82, 311, 370, 776, 18, 710, 818 SWRs per session in 6 WT
animals) i) Fraction of spikes in CA1 during SWRs as a function of the phase
of gamma in 5XFAD (green) and WT (black) mice for each animal (left) and the
mean and standard error across animals (right, n=2475, 1060, 3092,
25, 6521, 123 spikes during SWRs per session in 6 5XFAD mice and 360, 4741,
1564, 2961, 88, 3058, 4270 spikes during SWRs per session in 6 WT mice). j) SWR rate per non-theta period in 5XFAD (green) and WT (black)
mice for each animal (left) and all animals combined (right, ranksum test, p
< 10-10, n=117, 210, 151, 55, 100, 1 non-theta
periods per session in 6 5XFAD mice and 80, 68, 115, 95, 15, 159, 218
non-theta periods per session in 6 WT mice). k) The cumulative distribution of gamma power during large SWRs
(detection threshold greater than 6 standard deviations above the mean,
Methods) shows significantly smaller increases in 5XFAD (green) than WT
(black) mice (ranksum test, p<10-5, n=1000 SWRs
in 6 5XFAD mice and 1467 SWRs in 6 WT mice). l) Fraction of spikes as a function of the phase of gamma during
large SWRs (detection threshold greater than 6 standard deviations above the
mean, Methods), mean ± SEM (left) and histogram of the depth of
modulation of spiking (right) as a function of gamma phase in 3-month-old
5XFAD (green, n=6 mice) and WT (black, n=6 mice) mice
(ranksum test, bootstrap resampling p < 10-10,
n=2500 5XFAD spike-gamma phase distributions and 3000 WT
distributions). m) Power spectral density during 40 Hz stimulation (red, left),
random stimulation (blue, center), or no stimulation (black, right) of
FS-PV-interneurons in CA1 for each mouse (n=4 5XFAD mice with 169,
130, 240, 73 40 Hz, 143, 129, 150, 72 random, and 278, 380, 52, 215 no
stimulation periods per animal and n=3 WT mice with 65, 93, 91 40
Hz, 64, 93, 90 random, and 187, 276, 270 no stimulation periods per
animal). n) Above: Example raw LFP trace (above) and the
trace filtered for spikes (300-6000 Hz, below), with spikes indicated with
red stars after optogenetic stimulation (blue vertical lines).
Below: histogram of spikes per pulse after the onset of
the 1 ms laser pulse during 40 Hz stimulation (red), random stimulation
(blue), or no stimulation (black, n=345762 40 Hz, 301559 random
pulses, and 32350 randomly selected no stimulation times at least 500 ms
apart from 552 40 Hz, 543 random, and 1681 no stimulation periods in 4 5XFAD
and 3 WT mice). o) Histogram of the difference in firing rates between 40 Hz
stimulation and random stimulation periods shows that both types of
stimulation elicit similar amounts of spiking activity (Wilcoxon signed rank
test for zero median, p>0.6, n=538 stimulation periods from
4 5XFAD and 3 WT mice, n.s. indicates not significant). p) Multiunit firing rates per 40 Hz stimulation (red), random
stimulation (blue), and no stimulation (black) period for each animal. Box
and whisker plots show median (white lines in box) and quartiles (top and
bottom of box). In all animals firing rates between 40 Hz and random
stimulation were not significantly different, showing that the random
stimulation condition serves as a control for spiking activity (ranksum
tests for each animal, 3 WT and 4 5XFAD mice, p's>0.09,
n=87, 130, 8, 65, 93, 91, 73 40 Hz stimulation periods and 85, 129,
5, 64, 93, 90, 72 random stimulation periods per animal). We also examined
whether 40 Hz stimulation caused neuronal hyperactivity relative to no
stimulation, because according to a recent report, this could have negative
effects on neural circuit function. In most animals the firing rates between 40 Hz or
random stimulation and no stimulation were not significantly different
(ranksum tests for each animal, 2 WT and 2 5XFAD, p's>0.25,
n=8, 93, 91, 73 40 Hz stimulation periods and 15, 277, 270, 215
baseline periods per animal) or the firing rates during 40 Hz or random
stimulation were lower than during no stimulation (ranksum tests for each
animal, 1 WT and 1 5XFAD, p's<10-5, which is
significant when corrected for performing multiple comparisons,
n=130, 65 40 Hz stimulation periods and 379, 187 baseline periods
per animal) indicating that 40 Hz stimulation did not cause neuronal
hyperactivity. In one animal there was significantly more activity with 40
Hz or random stimulation than during baseline (ranksum test for 1 5XFAD,
mouse, p<10-5, n=87 40 Hz stimulation periods and
251 baseline periods per animal). Therefore in six out of seven animals we
see no evidence that the 40 Hz optogenetic stimulation of FS-PV-interneurons
causes hyperactivity.