Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lasts lifelong and causes noticeably higher premature mortality. Although the core symptoms and other behavioral deficits of ASD can persist or be deteriorated from early development to old age, how aging affects the behaviors and brain anatomy in ASD is largely unknown. DOCK4 is an ASD risk gene highly expressed in the hippocampus, and Dock4 knockout (KO) mice display ASD-like behaviors in adulthood (4- to 6-month-old). In this study, we evaluated the behavioral and hippocampal pathological changes of late-middle-aged (15- to 17-month-old) Dock4 male KO mice. Aged Dock4 KO mice continuously showed similar social deficit, elevated anxiety, and disrupted object location memory as observed in the adulthood, when compared to their wild-type (WT) littermates. Notably, Dock4 KO mice displayed an age-related decline of hippocampal dependent spatial memory, showing decreased spatial memory in Barnes maze than their WT littermates at late middle age. Morphological analysis from WT and Dock4 KO littermates revealed that Dock4 deficiency led to decreased mature neurons and oligodendrocytes but increased astrocytes in the hippocampus of late-middle-aged mice. Together, we report that ASD-like behaviors mostly persist into late-middle age in Dock4 KO mice, with specific alterations of spatial memory and hippocampal anatomy by age, thus providing new evidence for understanding age differences in behavioral deficits of ASD.
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References
Alvarez Cooper I, Beecher K, Chehrehasa F, Belmer A, Bartlett SE (2020) Tumour necrosis factor in neuroplasticity, neurogenesis and alcohol use disorder. Brain Plast 6(1):47–66. https://doi.org/10.3233/BPL-190095
Barker GRI, Warburton EC (2011) When is the hippocampus involved in recognition memory? J Neurosci 31(29):10721. https://doi.org/10.1523/JNEUROSCI.6413-10.2011
Bartsch T, Wulff P (2015) The hippocampus in aging and disease: from plasticity to vulnerability. Neuroscience 309:1–16. https://doi.org/10.1016/j.neuroscience.2015.07.084
Bishop-Fitzpatrick L, Rubenstein E (2019) The physical and mental health of middle aged and older adults on the autism spectrum and the impact of intellectual disability. Res Autism Spectr Disord 63:34–41. https://doi.org/10.1016/j.rasd.2019.01.001
Blaser H, Dostert C, Mak TW, Brenner D (2016) TNF and ROS crosstalk in inflammation. Trends Cell Biol 26(4):249–261. https://doi.org/10.1016/j.tcb.2015.12.002
Braden BB, Smith CJ, Thompson A, Glaspy TK, Wood E, Vatsa D, Abbott AE, McGee SC, Baxter LC (2017) Executive function and functional and structural brain differences in middle-age adults with autism spectrum disorder. Autism Res 10(12):1945–1959. https://doi.org/10.1002/aur.1842
Dietz PM, Rose CE, McArthur D, Maenner M (2020) National and state estimates of adults with autism spectrum disorder. J Autism Dev Disord 50(12):4258–4266. https://doi.org/10.1007/s10803-020-04494-4
Ecker C, Bookheimer SY, Murphy DGM (2015) Neuroimaging in autism spectrum disorder: brain structure and function across the lifespan. Lancet Neurology 14(11):1121–1134. https://doi.org/10.1016/S1474-4422(15)00050-2
El-Gaby M, Reeve HM, Lopes-dos-Santos V, Campo-Urriza N, Perestenko PV, Morley A, Strickland LAM, Lukács IP, Paulsen O, Dupret D (2021) An emergent neural coactivity code for dynamic memory. Nat Neurosci 24(5):694–704. https://doi.org/10.1038/s41593-021-00820-w
Fan X, Wheatley EG, Villeda SA (2017) Mechanisms of Hippocampal Aging and the Potential for Rejuvenation. Annu Rev Neurosci 40(1):251–272. https://doi.org/10.1146/annurev-neuro-072116-031357
Gennaccaro L, Fuchs C, Loi M, Pizzo R, Alvente S, Berteotti C, Lupori L, Sagona G, Galvani G, Gurgone A, Raspanti A, Medici G, Tassinari M, Trazzi S, Ren E, Rimondini R, Pizzorusso T, Giovanna Z, Maurizio G, Elisabetta C (2021) Age-related cognitive and motor decline in a mouse model of CDKL5 deficiency disorder is associated with increased neuronal senescence and death. Aging Dis 12(3):764–785. https://doi.org/10.14336/AD.2020.0827
Geurts HM, Pol SE, Lobbestael J, Simons CJP (2020) Executive functioning in 60+ autistic males: the discrepancy between experienced challenges and cognitive performance. J Autism Dev Disord 50(4):1380–1390. https://doi.org/10.1007/s10803-020-04368-9
Guo D, Yang X, Shi L (2020) Rho GTPase regulators and effectors in autism spectrum disorders: animal models and insights for therapeutics. Cells 9(4):835. https://doi.org/10.3390/cells9040835
Guo D, Peng Y, Wang L, Sun X, Wang X, Liang C, Yang X, Li S, Xu J, Ye W-C, Jiang B, Shi L (2021) Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. Mol Psychiatry 26(5):1505–1519. https://doi.org/10.1038/s41380-019-0472-7
Habbas S, Santello M, Becker D, Stubbe H, Zappia G, Liaudet N, Klaus Federica R, Kollias G, Fontana A, Pryce Christopher R, Suter T, Volterra A (2015) Neuroinflammatory TNFα impairs memory via astrocyte signaling. Cell 163(7):1730–1741. https://doi.org/10.1016/j.cell.2015.11.023
Hand BN, Angell AM, Harris L, Carpenter LA (2019) Prevalence of physical and mental health conditions in Medicare-enrolled, autistic older adults. Autism 24(3):755–764. https://doi.org/10.1177/1362361319890793
Hirvikoski T, Mittendorfer-Rutz E, Boman M, Larsson H, Lichtenstein P, Bölte S (2018) Premature mortality in autism spectrum disorder. Br J Psychiatry 208(3):232–238. https://doi.org/10.1192/bjp.bp.114.160192
Howlin P, Moss P, Savage S, Rutter M (2013) Social outcomes in mid- to later adulthood among individuals diagnosed with autism and average nonverbal iq as children. J Am Acad Child Adolesc Psychiatry 52(6):572-581.e571. https://doi.org/10.1016/j.jaac.2013.02.017
Howlin P, Savage S, Moss P, Tempier A, Rutter M (2014) Cognitive and language skills in adults with autism: a 40-year follow-up. J Child Psychol Psychiatry 55(1):49–58. https://doi.org/10.1111/jcpp.12115
Huang M, Liang C, Li S, Zhang J, Guo D, Zhao B, Liu Y, Peng Y, Xu J, Liu W, Guo G, Shi L (2020) Two autism/dyslexia linked variations of DOCK4 disrupt the gene function on Rac1/Rap1 activation, neurite outgrowth, and synapse development. Front Cell Neurosci 13:577. https://doi.org/10.3389/fncel.2019.00577
Iakoucheva LM, Muotri AR, Sebat J (2019) Getting to the cores of autism. Cell 178(6):1287–1298. https://doi.org/10.1016/j.cell.2019.07.037
Jasien JM, Daimon CM, Wang R, Shapiro BK, Martin B, Maudsley S (2014) The effects of aging on the BTBR mouse model of autism spectrum disorder. Front Aging Neurosci 6:225. https://doi.org/10.3389/fnagi.2014.00225
Jiménez JA, Ptacek TS, Tuttle AH, Schmid RS, Moy SS, Simon JM, Zylka MJ (2020) Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life. Molecular Autism 11(1):74. https://doi.org/10.1186/s13229-020-00369-8
Kipp M (2020) Oligodendrocyte physiology and pathology function. Cells 9(9):2078. https://doi.org/10.3390/cells9092078
Leonoudakis D, Zhao P, Beattie EC (2008) Rapid tumor necrosis factor α-induced exocytosis of glutamate receptor 2-lacking AMPA receptors to extrasynaptic plasma membrane potentiates excitotoxicity. J Neurosci 28(9):2119. https://doi.org/10.1523/JNEUROSCI.5159-07.2008
Lever AG, Geurts HM (2016) Psychiatric co-occurring symptoms and disorders in young, middle-aged, and older adults with autism spectrum disorder. J Autism Dev Disord 46(6):1916–1930. https://doi.org/10.1007/s10803-016-2722-8
Linke AC, Kinnear MK, Kohli JS, Fong CH, Lincoln AJ, Carper RA, Müller R-A (2020) Impaired motor skills and atypical functional connectivity of the sensorimotor system in 40- to 65-year-old adults with autism spectrum disorders. Neurobiol Aging 85:104–112. https://doi.org/10.1016/j.neurobiolaging.2019.09.018
Lord C, Bishop SL (2015) Recent advances in autism research as reflected in DSM-5 criteria for autism spectrum disorder. Annu Rev Clin Psychol 11(1):53–70. https://doi.org/10.1146/annurev-clinpsy-032814-112745
Ma X, Jiang G, Tian J, Liu M, Fang J, Xu Y, Song T (2021) Convergent and divergent functional connectivityalterations of hippocampal subregions between short-term and chronic insomnia disorder. Brain Imaging Behav 15(2):986–995. https://doi.org/10.1007/s11682-020-00306-6
Maenner MJ, Shaw KA, Bakian AV, Bilder DA, Durkin MS, Esler A, Furnier SM, Hallas L, Hall-Lande J, Hudson A, Hughes MM, Patrick M, Pierce K, Poynter JN, Salinas A, Shenouda J, Vehorn A, Warren Z, Constantino JN, DiRienzo M, Fitzgerald RT, Grzybowski A, Spivey MH, Pettygrove S, Zahorodny W, Ali A, Andrews JG, Baroud T, Gutierrez J, Hewitt A, Lee L-C, Lopez M, Mancilla KC, McArthur D, Schwenk YD, Washington A, Williams S, Cogswell ME (2021) Prevalence and characteristics of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, united states, 2018. Morb mortal wkly rep Surveill summ (Washington) 70(11):1–16. https://doi.org/10.15585/mmwr.ss7011a1
Makihara S, Morin S, Ferent J, Côté J-F, Yam PT, Charron F (2018) Polarized dock activity drives shh-mediated axon guidance. Dev Cell 46(4):410-425.e417. https://doi.org/10.1016/j.devcel.2018.07.007
Mason D, Ronald A, Ambler A, Caspi A, Houts R, Poulton R, Ramrakha S, Wertz J, Moffitt TE, Happé F (2021) Autistic traits are associated with faster pace of aging: evidence from the dunedin study at age 45. Autism Res 14(8):1684–1694. https://doi.org/10.1002/aur.2534
Matejuk A, Ransohoff RM (2020) Crosstalk between astrocytes and microglia: an overview. Front Immunol 11:1416. https://doi.org/10.3389/fimmu.2020.01416
Mukherjee C, Kling T, Russo B, Miebach K, Kess E, Schifferer M, Pedro LD, Weikert U, Fard MK, Kannaiyan N, Rossner M, Aicher M-L, Goebbels S, Nave K-A, Krämer-Albers E-M, Schneider A, Simons M (2020) Oligodendrocytes provide antioxidant defense function for neurons by secreting ferritin heavy chain. Cell Metab 32(2):259-272.e210. https://doi.org/10.1016/j.cmet.2020.05.019
Mygind L, Bergh MS, Tejsi V, Vaitheeswaran R, Lambertsen KL, Finsen B, Metaxas A (2021) Tumor necrosis factor (TNF) is required for spatial learning and memory in male mice under physiological, but not immune-challenged conditions. Cells. https://doi.org/10.3390/cells10030608
O’Connor R, van De Wouw M, Moloney GM, Ventura-Silva AP, O’Riordan K, Golubeva AV, Dinan TG, Schellekens H, Cryan JF (2021) Strain differences in behaviour and immunity in aged mice: relevance to autism. Behav Brain Res 399:113020. https://doi.org/10.1016/j.bbr.2020.113020
Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50(4):427–434. https://doi.org/10.1002/glia.20207
Prenderville JA, Kennedy PJ, Dinan TG, Cryan JF (2015) Adding fuel to the fire: the impact of stress on the ageing brain. Trends Neurosci 38(1):13–25. https://doi.org/10.1016/j.tins.2014.11.001
Ring M, Guillery-Girard B, Quinette P, Gaigg SB, Bowler DM (2020) Short-term memory span and cross-modality integration in younger and older adults with and without autism spectrum disorder. Autism Res 13(11):1970–1984. https://doi.org/10.1002/aur.2387
Sams Eleanor C (2021) Oligodendrocytes in the aging brain. Neuronal Signal 5(3):NS20210008. https://doi.org/10.1042/NS20210008
Shaw KA, Maenner MJ, Bakian AV, Bilder DA, Durkin MS, Furnier SM, Hughes MM, Patrick M, Pierce K, Salinas A, Shenouda J, Vehorn A, Warren Z, Zahorodny W, Constantino JN, DiRienzo M, Esler A, Fitzgerald RT, Grzybowski A, Hudson A, Spivey MH, Ali A, Andrews JG, Baroud T, Gutierrez J, Hallas L, Hall-Lande J, Hewitt A, Lee L-C, Lopez M, Mancilla KC, McArthur D, Pettygrove S, Poynter JN, Schwenk YD, Washington A, Williams S, Cogswell ME (2021) Early identification of autism spectrum disorder among children aged 4 years—autism and developmental disabilities monitoring network, 11 sites, united states, 2018. Morb mortal wkly rep Surveill summ (Washington) 70(10):1–14. https://doi.org/10.15585/mmwr.ss7010a1
Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-α. Nature 440(7087):1054–1059. https://doi.org/10.1038/nature04671
Strange BA, Witter MP, Lein ES, Moser EI (2014) Functional organization of the hippocampal longitudinal axis. Nat Rev Neurosci 15(10):655–669. https://doi.org/10.1038/nrn3785
Tse VWS, Crabtree J, Islam S, Stott J (2019) Comparing intellectual and memory abilities of older autistic adults with typically developing older adults using WAIS-IV and WMS-IV. J Autism Dev Disord 49(10):4123–4133. https://doi.org/10.1007/s10803-019-04122-w
Ueda S, Fujimoto S, Hiramoto K, Negishi M, Katoh H (2008) Dock4 regulates dendritic development in hippocampal neurons. J Neurosci Res 86(14):3052–3061. https://doi.org/10.1002/jnr.21763
Ueda S, Negishi M, Katoh H (2013) Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation. Mol Biol Cell 24(10):1602–1613. https://doi.org/10.1091/mbc.e12-11-0782
Uljarević M, Hedley D, Rose-Foley K, Magiati I, Cai RY, Dissanayake C, Richdale A, Trollor J (2020) Anxiety and depression from adolescence to old age in autism spectrum disorder. J Autism Dev Disord 50(9):3155–3165. https://doi.org/10.1007/s10803-019-04084-z
Vainchtein ID, Molofsky AV (2020) Astrocytes and microglia: in sickness and in health. Trends neurosci 43(3):144–154. https://doi.org/10.1016/j.tins.2020.01.003
Varghese M, Keshav N, Jacot-Descombes S, Warda T, Wicinski B, Dickstein DL, Harony-Nicolas H, De Rubeis S, Drapeau E, Buxbaum JD, Hof PR (2017) Autism spectrum disorder: neuropathology and animal models. Acta Neuropathol 134(4):537–566. https://doi.org/10.1007/s00401-017-1736-4
Velikonja T, Fett A-K, Velthorst E (2019) Patterns of nonsocial and social cognitive functioning in adults with autism spectrum disorder: a systematic review and meta-analysis. JAMA Psychiat 76(2):135–151. https://doi.org/10.1001/jamapsychiatry.2018.3645
Voss MW, Soto C, Yoo S, Sodoma M, Vivar C, van Praag H (2019) Exercise and hippocampal memory systems. Trends Cogn Sci 23(4):318–333. https://doi.org/10.1016/j.tics.2019.01.006
Xia B, Wei J, Ma X, Nehme A, Liong K, Cui Y, Chen C, Gallitano A, Ferguson D, Qiu S (2021) Conditional knockout of MET receptor tyrosine kinase in cortical excitatory neurons leads to enhanced learning and memory in young adult mice but early cognitive decline in older adult mice. Neurobiol Learn Mem 179:107397. https://doi.org/10.1016/j.nlm.2021.107397
Xiao Y, Peng Y, Wan J, Tang G, Chen Y, Tang J, Ye W-C, Ip NY, Shi L (2013) The atypical guanine nucleotide exchange factor dock4 regulates neurite differentiation through modulation of Rac1 GTPase and actin dynamics. J Biol Chem 288(27):20034–20045. https://doi.org/10.1074/jbc.M113.458612
Xu M, Ouyang Q, Gong J, Pescosolido MF, Pruett BS, Mishra S, Schmidt M, Jones RN, Gamsiz Uzun ED, Lizarraga SB, Morrow EM (2017) Mixed neurodevelopmental and neurodegenerative pathology in Nhe6-null mouse model of christianson syndrome. eneuro 4(6):ENEURO.0388-0317. https://doi.org/10.1523/eneuro.0388-17.2017
Yang L, Zou B, Xiong X, Pascual C, Xie J, Malik A, Xie J, Sakurai T, Xie X (2013) Hypocretin/orexin neurons contribute to hippocampus-dependent social memory and synaptic plasticity in mice. J Neurosci 33(12):5275. https://doi.org/10.1523/JNEUROSCI.3200-12.2013
Yang X, Guo D, Li K, Shi L (2021) Altered postnatal developmental patterns of ultrasonic vocalizations in Dock4 knockout mice. Behav Brain Res 406:113232. https://doi.org/10.1016/j.bbr.2021.113232
Zhou H, Xu X, Yan W, Zou X, Wu L, Luo X, Li T, Huang Y, Guan H, Chen X, Mao M, Xia K, Zhang L, Li E, Ge X, Zhang L, Li C, Zhang X, Zhou Y, Ding D, Shih A, Fombonne E, Zheng Y, Han J, Sun Z, Jiang Y-h, Wang Y, Team L-NS (2020) Prevalence of autism spectrum disorder in china: a nationwide multi-center population-based study among children aged 6 to 12 years. Neurosci Bull 36(9):961–971. https://doi.org/10.1007/s12264-020-00530-6
Zhu J-W, Jia W-Q, Zhou H, Li Y-F, Zou M-M, Wang Z-T, Wu B-S, Xu R-X (2021) Deficiency of TRIM32 impairs motor function and purkinje cells in mid-aged mice. Front in Aging Neurosci. https://doi.org/10.3389/fnagi.2021.697494
Acknowledgements
We thank colleagues and students in Shi Group of JNU-HKUST Joint Lab for Neuroscience and Innovative Drug Research for constructive discussions on this study. This study was supported by the Key-Area Research and Development Program of Guangdong Province (2019B030335001), the National Natural Science Foundation of China (82071535, 81971079, 82101240), Guangdong Basic and Applied Basic Research Foundation (2020A1515110570), and China Postdoctoral Science Foundation (2021M691245).
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This work was supported by the Key-Area Research and Development Program of Guangdong Province Grant No 2019B030335001, the National Natural Science Foundation of China Grant Nos 82071535, 81971079, 82101240, Guangdong Basic and Applied Basic Research Foundation Grant No 2020A1515110570, and China Postdoctoral Science Foundation Grant No 2021M691245.
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Conceptualization: DG, KL, LS; Resources: KL, LS. Methodology: XY, MG; Validation: DG, XC; Formal analysis: DG, XY, MG, XC, YT; Investigation: DG, XY, MG, XC, YT, LLS; Writing—Original Draft: DG, XY, MG; Writing—Review & Editing: DG, KL, LS; Visualization: DG, XY, KL, LS; Supervision: DG, KL, LS; Funding acquisition: DG, KL, LS. Project administration: LS.
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Guo, D., Yang, X., Gao, M. et al. Deficiency of Autism-Related Gene Dock4 Leads to Impaired Spatial Memory and Hippocampal Function in Mice at Late Middle Age. Cell Mol Neurobiol 43, 1129–1146 (2023). https://doi.org/10.1007/s10571-022-01233-4
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DOI: https://doi.org/10.1007/s10571-022-01233-4