Correlation between desynchrony of hippocampal neural activity and hyperlocomotion in the model mice of schizophrenia and therapeutic effects of aripiprazole

Abstract

Aims: The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear.

Methods: Mouse pups were injected with N-methyl-D-aspartate receptor antagonist (MK-801) or vehicle twice daily on postnatal days (PND) 7-11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity.

Results: We found that the hippocampal theta oscillations were enhanced in MK-801-treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK-801 treatment.

Conclusions: These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.

Keywords: aripiprazole; hippocampus; hyperlocomotion; neural activity; schizophrenia.

FIGURE 1

Effects of early postnatal MK‐801 treatment on locomotion and expression of c‐Fos in hippocampus. (A) The experimental timeline for vehicle or MK‐801 treatment and behavioral tests. (B) Movement trace diagrams of the vehicle and MK‐801‐treated mice in the OFT (the white box indicates the central area of the OFT). (C, D) Statistical charts of total traveled distance and the percent of time spent in the center in the OFT. Dots represent the values of individual mouse. Bars and ticks are means ± SD from eight mice (four male/four female) per group. (E) Representative images of c‐Fos (red) and DAPI (blue) in the dCA1, white arrows on c‐Fos/DAPI panel. (F) Quantification of the number of c‐Fos positive cells in dCA1 between vehicle and MK‐801‐treated mice. Values are from five mice (two male/three female) per group. *p < 0.05, **p < 0.01, ***p < 0.001, Student's t‐test.

FIGURE 2

Effects of early postnatal MK‐801 treatment on hippocampal spiking activities and LFP oscillations. (A) The timeline of the experimental procedures for in vivo electrophysiological recording. (B) Histological sections showing the location of the multi‐channel probe. (C) The example power spectra of LFP recorded from one vehicle (black line) and MK‐801‐treated mouse (dashed line). Gray shadings indicate the frequency bands of delta, theta, beta and gamma. (D–G) Statistical charts of the power of delta, theta, beta and gamma bands (n = 10; five male/five female). *p < 0.05, **p < 0.01, ***p < 0.001, Student's t‐test. (H, I) Statistical charts of spiking rate for RS unit (n = 37/32 from 10 vehicle/MK‐801‐treated mice; five male/five female) and FS unit (n = 34/39 from 10 vehicle/MK‐801‐treated mice; five male/five female). (J) Example LFP and simultaneously recorded two spiking activities. Black dots show one spiking activity phase‐locking with respect to hippocampal theta oscillations, whereas the other represented in gray dots does not. (K) Line plot showing spike‐LFP coherence for two examples from (I). (L, M) Probability distribution histogram of the peak frequency of spike‐LFP coherence in RS unit. (N) Line plot displaying cumulative distribution of coherence coefficients in RS unit. (O, P) Probability distribution histogram of the peak frequency of spike‐LFP coherence in FS unit. (Q) Line plot displaying cumulative distribution of coherence coefficients in FS unit.

FIGURE 3

In vivo calcium imaging in dCA1 and calcium transients during locomotion. (A) The timeline of the experimental procedures for in vivo calcium imaging. (B) Mice head‐fixed and allowed to run freely on a treadmill. (C) Immunohistological image showing GCaMP6s expression in the dCA1. (D, E) Representative calcium traces of vehicle and MK‐801‐treated mice. Each line represents the calcium transient of one cell.

FIGURE 4

Effects of early postnatal MK‐801 treatment on calcium activities of individual hippocampal neurons. (A, B) Raster plot of z‐scored calcium activities imaged from the dCA1 neurons of one example mouse. Blue line below showing locomotion speed. (C, D) Heat map displaying representative correlation matrices of calcium activities between pairs of neurons in vehicle and MK‐801‐treated mice. (E, F) Line plot displaying cumulative distribution of pairwise correlation coefficients of calcium activities between individual neurons, and between the neural calcium activities and locomotion speed. (G–I) Violin plots quantifying the number, amplitude, and decay of detected calcium transients. Values are from four mice (two male/two female) per group. ***p < 0.001, Student's t‐test.

FIGURE 5

Effects of ARI treatment on the hippocampal neural activities and hyperlocomotion in MK‐801‐treated mice. For neural electrophysiological activities, (A) timeline of the experimental procedures of electrophysiological recording, (B) theta power of LFP (n = 5; three male/two female), (C) gamma power of LFP (n = 5; three male/two female), (D) spiking rate of RS unit (n = 36/42 from eight vehicle/MK‐801‐treated mice; four male/four female), (E) spiking rate of FS unit (n = 34/28 from eight vehicle/MK‐801‐treated mice; four male/four female), (F) coherence coefficients between spiking activity of RS unit and theta oscillation and (G) coherence coefficients between spiking activity of FS unit and theta oscillation. For calcium dynamics, (H) timeline of the experimental procedures of calcium imaging, (I) number, (J), amplitude, and (K) decay of detected calcium transients, (L) pairwise correlation of calcium activities between individual neurons and (M) correlation coefficients between the calcium activities and locomotion speed (n = 4; two male/two female). For locomotor activity, (N) timeline of the experimental procedures of OFT, (O) total traveled distance in OFT (n = 5; three male/two female). *p < 0.05, **p < 0.01, ***p < 0.001, Two‐way ANOVA with Šídák's post‐hoc test.