Objective To observe the effects of early postnatal immune activation (EPIA) on social behaviors of male and female mice, and to explore the possible role of the functional state of astrocytes and microglia in this process. Methods Using lipopolysaccharide (LPS) induced EPIA mice as study subjects, mice were divided into the male-control, male-model, female-control, and female-model groups, each containing 10 mice (n=10). Behavioral tests were performed at 25 - 32 days of age, and the social behavior ability of mice was evaluated by open field test, three-chamber sociability test, and marble burying test. The expression levels of GFAP, IBA-1, TLR4, and NFκB p65 in the cortex and hippocampus were detected by Western blot (n=3). Results In behavioral tests, social index significantly decreased in LPS treatment group (F=14.907, P＜0.05). The interaction effect between treatment and sex was significant in the residence time (F =5.260, P<0.05) and the number of buried marbles (F=7.788, P<0.05). LPS treatment decreased the retention time of the central region in male mice (F=4.261, P<0.05), and increased the number of buried marbles in males (F=20.645, P<0.05). Western blot results showed that LPS treatment increased the expression of GFAP protein in the hippocampus (F=50.443, P<0.05) and cortex (F=30.116, P<0.05), as well as the expression of IBA-1 protein (F=21.844. P<0.05) and TLR4 protein (F=6.215, P<0.05) in the cortex. The results of NFκB p65 showed a significant interaction between treatment and sex in the cortex (F=6.558, P<0.05), and LPS increased the expression of NFκB p65 protein in the cortex in female mice (F=16.317, P<0.05). Conclusions EPIA is sufficient to induce sex-specific autism spectrum disorder (ASD)-like behavior and enhance astroglial and microglial reactivity in mice. ASD-like behavior induced by EPIA may be related to the TLR4/NFκB signaling pathway in the cortex.
Key words
autism spectrum disorder /
immune activation /
lipopolysaccharide /
neonatal mouse /
glial cells
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
References
[1] Carlezon WA, Kim W, Missig G, et al. Maternal and early postnatal immune activation produce sex-specific effects on autism-like behaviors and neuroimmune function in mice[J]. Sci Rep, 2019, 9(1): 16928.
[2] Smith CJ, Kingsbury MA, Dziabis JE, et al. Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number[J]. Brain Behav Immun, 2020, 90: 332-345.
[3] Linnerbauer M, Wheeler MA, Quintana FJ. Astrocyte crosstalk in CNS inflammation[J]. Neuron, 2020, 108(4): 608-622.
[4] Petrelli F, Pucci L, Bezzi P. Astrocytes and microglia and their potential link with autism spectrum disorders[J]. Front Neurosci, 2016, 10: 21.
[5] Pape K, Tamouza R, Leboyer M, et al. Immunoneuropsychiatry—novel perspectives on brain disorders[J]. Nat Rev Neurol, 2019, 15(6): 317-328.
[6] Rein B, Ma K, Yan Z. A standardized social preference protocol for measuring social deficits in mouse models of autism[J]. Nat Protoc, 2020, 15(10): 3464-3477.
[7] Santana-Santana M, Bayascas JR, Giménez-Llort L. Sex-dependent signatures, time frames and longitudinal fine-tuning of the marble burying test in normal and AD-pathological aging mice[J]. Biomedicines, 2021, 9(8): 994.
[8] Ellul P, Rosenzwajg M, Peyre H, et al. Regulatory T lymphocytes/Th17 lymphocytes imbalance in autism spectrum disorders: Evidence from a meta-analysis[J]. Mol Autism, 2021, 12: 1-7.
[9] De Giacomo A, Gargano CD, Simone M, et al. B and T immunoregulation:A new insight of B regulatory lymphocytes in autism spectrum disorder[J]. Front Neurosci, 2021, 15: 732611.
[10] Nadeem A, Ahmad SF, Al-Harbi NO, et al. Imbalance in pro-inflammatory and anti-inflammatory cytokines milieu in B cells of children with autism[J]. Mol Immunol, 2022, 141: 297-304.
[11] Kordulewska NK, Kostyra E, Piskorz-Ogórek K, et al. Serum cytokine levels in children with spectrum autism disorder: Differences in pro-and anti-inflammatory balance[J]. J Neuroimmunol, 2019, 337: 577066.
[12] Sabourin KR, Reynolds A, Schendel D, et al. Infections in children with autism spectrum disorder: Study to Explore Early Development (SEED)[J]. Autism Res, 2019, 12(1): 136-146.
[13] Hankittichai P, Buacheen P, Pitchakarn P, et al. Artocarpus lakoocha extract inhibits LPS-induced inflammatory response in RAW 264.7 macrophage cells[J]. Int J Mol Sci, 2020, 21(4): 1355.
[14] Ardalan M, Chumak T, Quist A, et al. Reelin cells and sex-dependent synaptopathology in autism following postnatal immune activation[J]. Br J Pharmacol, 2022, 179(17): 4400-4422.
[15] McCarthy MM. Sex differences in neuroimmunity as an inherent risk factor[J]. Neuropsychopharmacology, 2019, 44(1): 38-44.
[16] DiStasio MM, Nagakura I, Nadler MJ, et al. T lymphocytes and cytotoxic astrocyte blebs correlate across autism brains[J]. Ann Neurol, 2019, 86(6): 885-898.
[17] Crawford JD, Chandley MJ, Szebeni K, et al. Elevated GFAP protein in anterior cingulate cortical white matter in males with autism spectrum disorder[J]. Autism Res, 2015, 8(6): 649-657.
[18] Liao X, Yang J, Wang H, et al. Microglia mediated neuroinflammation in autism spectrum disorder[J]. J Psychiatr Res, 2020, 130: 167-176.
[19] Barón-Mendoza I, García O, Calvo-Ochoa E, et al. Alterations in neuronal cytoskeletal and astrocytic proteins content in the brain of the autistic-like mouse strain C58/J[J]. Neurosci Lett, 2018, 682: 32-38.
[20] Nadeem A, Ahmad SF, Bakheet SA, et al. Toll-like receptor 4 signaling is associated with upregulated NADPH oxidase expression in peripheral T cells of children with autism[J]. Brain Behav Immun, 2017, 61: 146-154.
[21] Xiao L, Yan J, Feng D, et al. Critical role of TLR4 on the microglia activation induced by maternal LPS exposure leading to ASD-like behavior of offspring[J]. Front Cell Dev Biol, 2021, 9: 634837.
PDF(3649 KB)
