Fig. 4: Behavioral characterization of mice lacking NR1 in oligodendrocytes suggests participation of oligodendroglial NMDAR in NMDAR1-AB effects.
A Experimental outline of the study on female C57Bl/6 CnpCre+/−:NR1flox/flox (cKO) mice and their NR1flox/flox littermate controls (n = 16 each). Note that distinct behavioral paradigms were additionally tested in WT (n = 9) and CnpCre+/− (n = 7) mice, to separate a potential impact of heterozygous Cnp deficiency from loss of oligodendroglial NR1. B Overall activity in IntelliCage paradigms and C MTT performance of cKO (n = 13–14) does not differ from NR1flox/flox controls (n = 15), as demonstrated by trend lines (right), calculated by linear regression (GraphPad Prism 9 Software, San Diego, CA, USA). All slopes were non-zero (p < 0.001), documenting successful execution and MTT learning; similar MTT capabilities in cKO and control mice, p(slope)=0.345 (compare Fig. 1C, D). D–I Unaffected spatial memory and reversal learning in Morris water maze (MWM) during cued, hidden, and relocated platform training as well as during first and second probe trials. No differences were observed regarding the time spent in (G) or the number of visits to (H) the target quadrant. Overall locomotion was unaffected in cKO mice (I); n = 15 controls; n = 16 cKO; repeated measure mixed-model ANOVA revealed successful learning of the task, irrespective of genotype, with a significant main effect of time at all stages (p < 0.001). No significant time × genotype interaction was observed during the cued (p = 0.235), hidden (p = 0.654), or relocated (p = 0.211) platform training. J Motor coordination during beam balance is impaired in female cKO mice at the age of 8 months (n = 15) versus controls (n = 15); as well as K in a separate cohort of older females (12 months; n = 10 per genotype). L CnpCre+/− mice are not affected (n = 9 and 7 for WT and CnpCre+/−, respectively). M Motor performance and learning in the rotarod is impaired in female cKO mice at the age of 3 months (n = 16 and 15 for control and cKO, respectively) as well as N in a separate cohort of aged females (n = 12 and 10, respectively). O Motor learning is unaffected in CnpCre+/− mice; one-sided Welch’s corrected t-test. P Motor-cognitive abilities during 4 h of CRW (complex running wheel) performance is impaired in cKO mice but normal in CnpCre+/−; n = 8 per genotype; photographs of the CRW setup show omitted bars of CRW, demanding mice to adapt to irregular wheel pattern, i.e., requesting motor-cognitive performance; two-tailed unpaired Welch’s corrected t-test or Mann–Whitney U tests; mean ± SEM.
