Figure 6. Schizophrenia-derived human glial chimeras have significant behavioral abnormalities.
A–E, Behavioral tests were performed in mice chimerized with one of 3 SCZ or 3 control hGPC lines, each line from a different patient. 7–20 recipient mice were tested per cell line, males and females equally. A, Prepulse inhibition Normally-myelinated rag1−/− mice engrafted with SCZ hGPCs had reduced auditory pre-pulse inhibition (PPI) at all volumes of pre-pulse (A). The extent of PPI differed significantly between control (n=13) and SCZ (n=27) hGPC-engrafted animals (p=0.0008 by ANOVA, F=11.76 [1,114]). B. Elevated Plus Maze Left panel, representative heat maps of the cumulated movement of a mouse engrafted with SCZ hGPCs, relative to its matched normal hGPC-engrafted control, in the elevated plus maze, a test designed to assess anxiety, in which preference for enclosed space and avoidance of open height suggests greater anxiety. Right panel, Mice engrafted with hGPCs from 3 SCZ patients (12 implanted mice each, for n=36 mice total) spent more time in the closed maze arms than did control-engrafted mice (n=36, also derived from 3 patients) (p=0.036, 2-tailed t test). C. Sucrose Preference SCZ GPC-engrafted mice were less likely to prefer sweetened water, suggesting relative anhedonia (p=0.02, Mann-Whitney t-test; n=30 mice derived from 3 SCZ lines; n=17 mice from 3 control lines). D. 3-Chamber Socialization Test Mice engrafted with hGPCs were placed into the middle chamber of a box divided into 3 compartments, one holding an empty cage (bottom, “X” in D) and one containing an unfamiliar mouse (top, filled white circle), then video-tracked for 10 minutes. Mice engrafted with SCZ hGPCs (right heat-map) avoided strangers more than did control mice (left heat-map), spending less time with strangers whether analyzed as the proportion of time spent with the stranger mouse relative to the empty cage (left bar graph; p=0.005) or the net amount of time spent with the stranger mouse (right bar graph; p=0.02); 3 SCZ lines, 39 mice; 4 control lines, 52 mice). E. Novel Object Recognition Mice engrafted with SCZ hGPCs showed significantly poorer novel object recognition (p=0.0006; 3 SCZ lines, 19 mice; 3 control lines, 28 mice).
F–G. The diurnal activity and sleep patterns of adult mice (70–80 weeks old) engrafted neonatally with either SCZ or CTRL hGPCs were assessed for 72 hrs in closed chambers (Noldus Ethovision), under continuous video recording. F. The average distance traveled in meters/hr over a 72 hr period was calculated and compared between CTRL mice (gray fill, n=8 mice; lines 22 and 17) and SCZ mice (purple fill; n=10, line 52). Time of day is shown as a 24-hour cycle, with the dark phase indicated by gray background shading. The SCZ mice were significantly more active throughout the observation period than CTRL-engrafted mice (p<0.0001, ANOVA, F=19.32 [1,851]. G. Left, Sample heat-maps of one hour of activity during the light phase (16:00 hrs, 2nd day in box), the normal period of sleep for mice. The control mouse (left), remains inactive for the entire hour, while the SCZ mouse moves about the cage during much of the hour. Right, The SCZ mice exhibited sleep patterns that were fragmented into bouts of shorter duration than their normal hGPC- chimeric controls (p=0.0026 by ANOVA, F=12.08 [1,24]. Means ± SEM; unpaired, two-tailed Welch-corrected t-tests.