Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy

Altered firing properties of CA1 pyramidal neurons in behaving 7- to 8-month-old rTg4510 mice. a, Scatter plot (left) represents the waveform energies of extracellular APs recorded on two channels of a representative WT tetrode. Colors highlight clusters of APs discharged by individual neurons. Nonclustered APs have been omitted for clarity. Mean AP waveforms on each tetrode channel are displayed for the red unit cluster (circled). Calibration: 100 μV, 250 μs. Right, Spike-train autocorrelation for the red unit cluster. Note the prominent peak in the 0–50 ms autocorrelation (inset), illustrating the tendency for the cell to burst fire, and the ∼100 ms (theta) periodicity. b, As for a for a representative rTg4510 tetrode. Note the lack of obvious ∼100 ms periodicity in the blue unit cluster autocorrelation and the reduced prominence of a peak at short latency lags. Calibration: 100 μV, 250 μs. c–f, Cumulative frequency plots illustrating the distributions of WT (n = 21) and rTg4510 (n = 42) CA1-PN spike widths (c), firing rates (d), complex spike indices (e), and theta modulation indices (f). g, Lap-by-lap raster plots for the circled WT cell in a and two other representative cells recorded in two different WT mice. Track position is plotted on the abscissa. Arrows indicate the direction of track traversal. Each tick indicates the firing position of an AP. The averaged firing rate map is plotted below. h, As for g for the circled rTg4510 cell in b and two other representative cells recorded in two different rTg4510 mice. i–k, Cumulative frequency plots illustrating the distributions of WT (n = 36 trajectories) and rTg4510 (n = 61 trajectories) CA1-PN spatial information indices (i), firing field sizes (j), and lap-by-lap rate stabilities (k). c–f, i–k, Inset, Box plots represent the median, first and third quartiles, and 99% confidence limits. Line plots (normally distributed data) represent the mean ± SD. ns, Not significant at p > 0.05. *p < 0.05. **p < 0.01. ***p < 0.005.

Faster membrane time constant and increased I_h-mediated sag potential in rTg4510 CA1 pyramidal neurons. a, Left, Full-scale mean peak normalized traces (WT, black; rTg4510, blue) in response to 500 ms, −100 pA current injection. Right, Initial response on a larger time scale reveals the difference in τ_M more clearly. Shaded areas represent the SEM. b, Scatter plots represent membrane time constant (τ_M) and percentage sag from all recorded neurons (open symbols). Mean (filled symbols), SEM (box), and median (central line) are shown on the right. c, The number of action potentials elicited by 500 ms depolarizing current injection steps was not different between WT and rTg4510 CA1-PNs. d, Instantaneous frequency between consecutive spike pairs in response to 500 ms, 300 pA depolarizing current injection steps reveals no significant differences in firing patterns between genotypes. Inset, Representative example trace from a rTg4510 CA1-PN showing the initial high-frequency burst of action potentials followed by accommodation to ∼35 Hz. n = 39 WT and n = 27 rTg4510 CA1-PNs. *p < 0.05.

Resonance properties are altered in rTg4510 CA1 pyramidal neurons. a, Representative traces from WT (top) and rTg4510 (bottom) CA1-PNs showing the ZAP current protocol and corresponding voltage responses at −76, −82, and −88 mV. b, Impedance (Z) profiles (bottom) are calculated by dividing the FFT of the voltage response (top) by the FFT of the current injection (middle). Red line indicates the smoothed Z profile (bottom). c, d, Peak resonance frequency (c) and strength of resonance (Q; d) were significantly higher in rTg4510 CA1-PNs compared with WT. Data are mean ± SEM from n = 24 WT and n = 16 rTg4510 CA1-PNs. *p < 0.05. ***p < 0.005.

Changes in membrane capacitance are sufficient to produce experimentally observed changes in intrinsic membrane properties. a, Simulated voltage response to a current stimulus in a Hodgkin-Huxley style single compartment model of a CA1 pyramidal neuron. When the simulated membrane capacitance (C_M) was systematically increased (lighter red traces) or decreased (darker traces), differences in the voltage response were observed, which were particularly evident during the initial charging curves (shown on an expanded time-base in the bottom). b, The membrane time constant (τ_M, top) and percentage sag (middle) were decreased and increased, respectively, in response to a reduction in C_M. Furthermore, the maximal rate of rise of simulated action potentials (bottom) was also altered in a manner consistent with experimentally observed changes in rTg4510 CA1-PNs (Table 1). c, d, Peak membrane resonance frequency (c) and resonance quotient (Q; d) are also increased in response to decreased membrane capacitance (and vice versa). As observed experimentally, these effects are voltage-dependent.

Basal synaptic transmission and LTP in the Schaffer collateral and temporoammonic pathways. a, Schematic representation of the hippocampus showing approximate positions of stimulating and recording electrodes. SR, Stratum radiatum; SLM, stratum lacunosum moleculare; DG, dentate gyrus. b, Basal synaptic transmission is reduced in the SC pathway (left) but unaltered in the TA pathway (right) in slices from rTg4510 mice compared with WT. c, TBS-induced LTP is unaffected by genotype in the SC pathway (top) but significantly reduced in the TA pathway (bottom) in rTg4510 slices compared with WT. Left, Representative traces from baseline (1) and 60 min after TBS (2) from WT (black) and rTg4510 (blue) slices. Stimulus artifacts were removed for clarity. Right, Time course of normalized fEPSP slope (SC) or amplitude (TA) (see Materials and Methods) following TBS. SC, n = 10 WT and n = 11 rTg4510 slices; TA, n = 11 WT and n = 8 rTg4510 slices. ns, Not significant at p > 0.05. **p < 0.01.