Fig 1: Ifnar1–/– leads to PDD-like neuropathology and behavior. A Immunohistochemical (IHC) images and collective quantification of NeuN+ cells per mm2 in 6-month-old Wt, Ifnb–/–, and Ifnar1–/– cortex, hippocampus, and olfactory bulb as %Wt (n = 3–4 per genotype). ****P < 0.0001 by one-way ANOVA and Bonferroni’s post hoc correction test. Scale bars, 50 µm. IHC images and quantifications of tyrosine hydroxylase (TH)+ DA neurons and neurites in 3-month-old Wt versus Ifnar1–/– (B) substantia nigra and (C) striatum. (n = 4 per genotype). *P < 0.05 and **P < 0.01 by unpaired t-test. Scale bars, 200 µm (substantia nigra), 20 µm (insert), and 1 mm (striatum). D IHC (left) and immunogold-labelled (white arrows) TEM images (right) for pα-syn or pTau of Lewy body (LB)-like inclusions in 12-month-old Ifnar1−/−thalamus. Nu = nucleus. Scale bars, 5 µm (IHC) and 500 nm (TEM). E TEM micrograph of immunogold-labelled Aβ1–16 (white arrows) in fibrillar structures (black arrows) in 12-mo Ifnar1−/− thalamus. F Representative images of 12-month-old 5xFAD, Wt, and Ifnar1−/− cortex stained for Aβ1–16, with extracellular Aβ+ plaques per mm2 cortex quantified in Wt versus Ifnar1−/− mice (n = 4–7 per genotype). Scale bars, 50 µm. G Wire hang performances of 3-month-old mice (n = 10–16 per genotype). *P < 0.05 and **P < 0.01 by one-way ANOVA and Tukey’s post hoc correction test. H, I Barnes maze results of 12-month-old mice (n = 6–10 per genotype). H Barnes maze spatial learning performances. ##P < 0.01 for training effect and §P < 0.05 for genotype effect by two-way ANOVA. Genotype effect vs Wt *P < 0.05 and **P < 0.01 by Tukey’s post hoc test. I Memory probe on the Barnes maze as percent total test time spent in the escape zone. *P < 0.05 and **P < 0.01 by one-way ANOVA and Tukey’s post hoc correction test. J Novelty-suppressed feeding test results of 3-month-old mice (n = 8–9 per genotype), showing latency to first bite (seconds, s), amount of food consumed (grams, g), and eating duration (s). K Sucrose preference test results of 6-month-old Wt and Ifnar1−/− mice (n = 10–15 per genotype), comparing total liquid intake per mouse weight (g), sucrose intake per mouse weight (g), and sucrose preference ratio over water. *P < 0.05 and ** P < 0.01 by unpaired t-test. L Rearing activity of 3-month-old Wt, Ifnb–/–, and Ifnar1–/– mice (n = 17–20 per genotype). M Climbing activity of 3-month-old mice (n = 17–20 per genotype), quantified by latency to first climbing event (s) and number of climbing events. N Open field (OF) performance of 3-month-old mice as cumulative time (s) spent in maze center (n = 17–20 per genotype). O Elevated plus maze (EPM) performances of 3-month-old mice (n = 17–20 per genotype). Time spent in the maze open arms (top diagram, left graph) and number of side edge investigations (bottom diagram, right graph) were quantified. P Heat-induced tail flick latencies (nociception) of 3-month-old mice (n = 17–20 per genotype) as %Wt. Q Gene expression of cytokines IL-1b, IL-6, IL-12, and TGF-β by qPCR in 3-month-old mouse brain, shown as Log2FC of Wt (n = 3 per genotype). **P < 0.01, ***P < 0.001, and ****P < 0.0001 by two-way ANOVA and Tukey’s post hoc correction test. R IF images and quantification of TNF-ɑ+Iba1+ as %total Iba1+ microglia in the hippocampus of 9-month-old Wt, Ifnb–/–, and Ifnar1–/– mice (n = 3 per genotype). Previously published (12) Wt and Ifnb–/–data (blue text) were generated concurrently with the Ifnar1–/– data shown and included for comparison. ***P < 0.001 and ****P < 0.0001 by one-way ANOVA and Bonferroni’s post hoc correction test. Scale bars, 25 µm. S Representative IHC images and quantifications Mac-3+ microglia (black arrows) per mm2 in Wt vs Ifnar1−/− cortex (n = 4–7 per genotype). Scale bars, 100 µm; insert, 10 µm. *P < 0.05 by unpaired t-test. T IF images of GFAP+ astrocytes, Iba1+ microglia, or CD31+ endothelial cells (green) associated with Aβ+ (red) aggregates (white arrows) in 12-month-old Ifnar1−/− cortex. DAPI = blue. Scale bars, 25 µm. Data in all graphs are mean ± SEM