Treadmill Exercise Prevents Decline in Spatial Learning and Memory in 3×Tg-AD Mice through Enhancement of Structural Synaptic Plasticity of the Hippocampus and Prefrontal Cortex

Lianwei Mu, Jiajia Cai, Boya Gu, Laikang Yu, Cui Li, Qing-Song Liu, Li Zhao, Lianwei Mu, Jiajia Cai, Boya Gu, Laikang Yu, Cui Li, Qing-Song Liu, Li Zhao

Abstract

Alzheimer's disease (AD) is characterized by deficits in learning and memory. A pathological feature of AD is the alterations in the number and size of synapses, axon length, dendritic complexity, and dendritic spine numbers in the hippocampus and prefrontal cortex. Treadmill exercise can enhance synaptic plasticity in mouse or rat models of stroke, ischemia, and dementia. The aim of this study was to examine the effects of treadmill exercise on learning and memory, and structural synaptic plasticity in 3×Tg-AD mice, a mouse model of AD. Here, we show that 12 weeks treadmill exercise beginning in three-month-old mice improves spatial working memory in six-month-old 3×Tg-AD mice, while non-exercise six-month-old 3×Tg-AD mice exhibited impaired spatial working memory. To investigate potential mechanisms for the treadmill exercise-induced improvement of spatial learning and memory, we examined structural synaptic plasticity in the hippocampus and prefrontal cortex of six-month-old 3×Tg-AD mice that had undergone 12 weeks of treadmill exercise. We found that treadmill exercise led to increases in synapse numbers, synaptic structural parameters, the expression of synaptophysin (Syn, a presynaptic marker), the axon length, dendritic complexity, and the number of dendritic spines in 3×Tg-AD mice and restored these parameters to similar levels of non-Tg control mice without treadmill exercise. In addition, treadmill exercise also improved these parameters in non-Tg control mice. Strengthening structural synaptic plasticity may represent a potential mechanism by which treadmill exercise prevents decline in spatial learning and memory and synapse loss in 3×Tg-AD mice.

Keywords: 3×Tg-AD mice; dendritic spines; exercise; memory; structural synaptic plasticity; synaptic.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Treadmill exercise prevents decline in spatial learning and memory in 3×Tg-AD mice. (A) Timeline of treadmill exercise or non-exercise control, behavioral test and histological test. (B) The percentage of working memory errors on day 5 and day 6 was significantly increased in the 3×Tg-AD mice compared to the Non-Tg control group (B; ** p < 0.01, n = 10 mice). The increase in the percentage of working memory errors was prevented by treadmill exercise pretreatments (B; ## p < 0.01, n = 10 mice). (C) There were no significant effects on the percentage of reference memory errors between Non-Tg control, Non-Tg exercise, 3×Tg-AD control, and 3×Tg-AD exercise mice (C; p > 0.05, n = 10 mice).
Figure 2
Figure 2
Treadmill exercise increases synapse numbers of hippocampus and prefrontal cortex in 3×Tg-AD mice. (A) Representative electron microscope imaging of hippocampus and prefrontal cortex in non-Tg control, non-Tg exercise, 3×Tg-AD control, and 3×Tg-AD exercise mice. The synapses are marked by the blue arrowheads. Red box represents an enlarged synapse. An expanded, high magnification view of synapses in the prefrontal cortex is shown in the red square box in the bottom. (B,C) The synapse numbers of hippocampus (B) and prefrontal cortex (C) were significantly decreased in the 3×Tg-AD control group compared to the non-Tg control group (*** p < 0.001, n = 6 image sections), and this decrease was blocked by treadmill exercise pretreatment both in the hippocampus (B) and prefrontal cortex (C) (*** p < 0.001, n = 6 image sections). Treadmill exercise pretreatment increased the synapse numbers of the hippocampus (B) and prefrontal cortex (C) in non-Tg mice (** p < 0.01, n = 6 image sections). Each data set was obtained from 4 mice.
Figure 3
Figure 3
Treadmill exercise improves synaptic structural parameters of the hippocampus and prefrontal cortex in 3×Tg-AD mice. (A) A representative measurement of synaptic structural parameters. The formula R = a/2 + b2/8a, where b is the line joining the two ends of the postsynaptic thickening and a is the perpendicular distance from the postsynaptic membrane to b, was used to determine synaptic curvature. (B,C) The length of the synaptic active zone of hippocampus (B) and prefrontal cortex (C) was significantly decreased in the 3×Tg-AD control group compared to the non-Tg control group (*** p < 0.001, n = 12–15 synapses), and this decrease was blocked by treadmill exercise pretreatment both in the hippocampus and prefrontal cortex (*** p < 0.001, n = 12–15). (D,E) The width of the synaptic cleft of the hippocampus (D) and prefrontal cortex (E) was significantly increased in the 3×Tg-AD control group compared to the non-Tg control group (*** p < 0.001, n = 12–15 synapses), and this increase was blocked by treadmill exercise pretreatment both in the hippocampus (D; *** p < 0.001, n = 12–15 synapses) and prefrontal cortex (E; ** p < 0.01, n = 12–15). (F,G) The synaptic curvature of the hippocampus (F; *** p < 0.001, n = 12–15), and prefrontal cortex (G; ** p < 0.01, n = 12–15) was significantly decreased in the 3×Tg-AD control group compared to the non-Tg control group, and this decrease was blocked by treadmill exercise pretreatment both in the hippocampus (F; ** p < 0.01, n = 12–15) and prefrontal cortex (G; *** p < 0.001, n = 12–15). (H,I) The thickness of postsynaptic density of hippocampus (H) and prefrontal cortex (I) was significantly decreased in the 3×Tg-AD control group compared to the non-Tg control group (*** p < 0.001, n = 12–15), and this decrease was blocked by treadmill exercise pretreatment both in the hippocampus (H; ** p < 0.01, n = 12–15) and prefrontal cortex (I; *** p < 0.001, n = 12–15). Each data set consisted of 12 and 15 synapses from 4 mice each group.
Figure 4
Figure 4
Treadmill exercise facilitates the expression of Syn and PSD95 of hippocampus and prefrontal cortex in 3×Tg-AD mice. (A) Representative western blots for Syn, PSD95, and GAPDH of hippocampus and prefrontal cortex homogenates were prepared from these four groups of mice. (B,C) Summarized data showed that Syn of hippocampus (B; * p < 0.05, n = 6) and prefrontal cortex (C; ** p < 0.01, n = 6) were significantly decreased in the 3×Tg-AD control group compared to the non-Tg control group and this decrease was blocked by treadmill exercise pretreatment both in the hippocampus (B) and prefrontal cortex (C) (** p < 0.01, n = 6). (D,E) There were no significant effects on the PSD95 between non-Tg control, non-Tg exercise, 3×Tg-AD control, and 3×Tg-AD exercise mice in the hippocampus (D; p > 0.05, n = 6) and prefrontal cortex (E; p > 0.05, n = 6). Immunoreactivity was normalized to GAPDH and presented as the percentage of the non-Tg control group. Each data set was obtained from 3 mice.
Figure 5
Figure 5
Treadmill exercise enhance the axon length and dendritic complexity of the Hippocampus and prefrontal cortex in 3×Tg-AD mice. (A) Representative Golgi staining images of hippocampus and prefrontal cortex in non-Tg control, non-Tg exercise, 3×Tg-AD control, and 3×Tg-AD exercise mice. (B,C) Axon length of hippocampus (B) and prefrontal cortex (C) were significantly decreased in the 3×Tg-AD control group compared to the non-Tg control group (** p < 0.01, n = 9–13 image sections, 3–5 cells/image section) and this decrease was blocked by treadmill exercise pretreatment both in the hippocampus (B) and prefrontal cortex (C) (** p < 0.01, n = 9–13). Treadmill exercise increased the axon length in the hippocampus (B) and prefrontal cortex (C) in non-Tg mice (* p < 0.05, n = 9–13 image sections). (D,E) Dendritic complexity of hippocampus (D) and prefrontal cortex (E) were significantly decreased in the 3×Tg-AD control group compared to the non-Tg control group (** p < 0.01, n = 9–13 image sections) and this decrease was blocked by treadmill exercise pretreatment both in the hippocampus (D) and prefrontal cortex (E) (** p < 0.01, n = 9–13). Treadmill exercise increased the dendritic complexity in the hippocampus (D) and prefrontal cortex (E) in non-Tg mice (* p < 0.05, n = 9–13 image sections). Each data set was obtained from 3 mice.
Figure 6
Figure 6
Treadmill exercise improves the dendritic spines numbers of hippocampus and prefrontal cortex in 3×Tg-AD mice. (A) Representative Golgi staining images of the secondary dendrites of the CA1 pyramidal neurons in the hippocampus and layer V pyramidal neurons prefrontal cortex in non-Tg control, non-Tg exercise, 3×Tg-AD control, and 3×Tg-AD exercise mice. The dendritic spines in rectangles, triangles, and circles are thin, mushroom, and stubby dendritic spines, respectively. (B,C) The spines numbers of hippocampus (B) and prefrontal cortex (C) were significantly decreased in the 3×Tg-AD control group compared to the non-Tg control group (*** p < 0.001, n = 8), and this decrease was blocked by treadmill exercise pretreatment both in the hippocampus (B) and prefrontal cortex (C) (*** p < 0.001, n = 8 dendrites, respectively). Treadmill exercise pretreatment increased the spines numbers of the hippocampus (B) and prefrontal cortex (C) in non-Tg mice (** p < 0.01, n = 8 dendrites, respectively). (D,E) The thin spines of the hippocampus (D) and prefrontal cortex (E) were significantly decreased in the 3×Tg-AD control group compared to the non-Tg control group (*** p < 0.001, n = 8), and this decrease was blocked by treadmill exercise pretreatment both in the hippocampus (D) and prefrontal cortex (E) (*** p < 0.001, n = 8). Treadmill exercise pretreatment increased the spines numbers of the hippocampus (D; ** p < 0.01, n = 8) and prefrontal cortex (E; * p < 0.05, n = 8) in non-Tg mice. (F–I) The mushrooms (** p < 0.01, n = 8), and stubby spines (*** p < 0.001, n = 8) of prefrontal cortex (G,I) were significantly decreased in the 3×Tg-AD control group compared to the non-Tg control group, and this decrease was blocked by treadmill exercise pretreatment both in the prefrontal cortex (*** p < 0.001, n = 8). Treadmill exercise pretreatment increased the mushrooms (** p < 0.01, n = 8) and stubby spines (* p < 0.05, n = 8) of the prefrontal cortex (G,I) in non-Tg mice. There were no significant effects on the mushrooms and stubby spines of the hippocampus between non-Tg control, non-Tg exercise, 3×Tg-AD control, and 3×Tg-AD exercise mice (F,H; p > 0.05, n = 8). Each data set was obtained from 3 mice.

References

    1. Blennow K., de Leon M.J., Zetterberg H. Alzheimer’s disease. Lancet. 2006;368:387–403. doi: 10.1016/S0140-6736(06)69113-7.
    1. Jahn H. Memory loss in Alzheimer’s disease. Dialogues Clin. Neurosci. 2013;15:445–454. doi: 10.31887/DCNS.2013.15.4/hjahn.
    1. Glenner G.G., Wong C.W. Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 1984;120:885–890. doi: 10.1016/S0006-291X(84)80190-4.
    1. Grundke-Iqbal I., Iqbal K., Tung Y.C., Quinlan M., Wisniewski H.M., Binder L.I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. USA. 1986;83:4913–4917. doi: 10.1073/pnas.83.13.4913.
    1. Yoon T., Okada J., Jung M.W., Kim J.J. Prefrontal cortex and hippocampus subserve different components of working memory in rats. Learn. Mem. 2008;15:97–105. doi: 10.1101/lm.850808.
    1. Laroche S., Davis S., Jay T.M. Plasticity at hippocampal to prefrontal cortex synapses: Dual roles in working memory and consolidation. Hippocampus. 2000;10:438–446. doi: 10.1002/1098-1063(2000)10:4<438::AID-HIPO10>;2-3.
    1. Puzzo D., Argyrousi E.K., Staniszewski A., Zhang H., Calcagno E., Zuccarello E., Acquarone E., Fa M., Li Puma D.D., Grassi C., et al. Tau is not necessary for amyloid-β-induced synaptic and memory impairments. J. Clin. Investig. 2020;130:4831–4844. doi: 10.1172/JCI137040.
    1. Selkoe D.J. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav. Brain Res. 2008;192:106–113. doi: 10.1016/j.bbr.2008.02.016.
    1. Shankar G.M., Li S., Mehta T.H., Garcia-Munoz A., Shepardson N.E., Smith I., Brett F.M., Farrell M.A., Rowan M.J., Lemere C.A., et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat. Med. 2008;14:837–842. doi: 10.1038/nm1782.
    1. Laurén J., Gimbel D.A., Nygaard H.B., Gilbert J.W., Strittmatter S.M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009;457:1128–1132. doi: 10.1038/nature07761.
    1. Liu X.J., Yuan L., Yang D., Han W.N., Li Q.S., Yang W., Liu Q.S., Qi J.S. Melatonin protects against amyloid-beta-induced impairments of hippocampal LTP and spatial learning in rats. Synapse. 2013;67:626–636. doi: 10.1002/syn.21677.
    1. Arroyo-García L.E., Isla A.G., Andrade-Talavera Y., Balleza-Tapia H., Loera-Valencia R., Alvarez-Jimenez L., Pizzirusso G., Tambaro S., Nilsson P., Fisahn A. Impaired spike-gamma coupling of area CA3 fast-spiking interneurons as the earliest functional impairment in the App(NL-G-F) mouse model of Alzheimer’s disease. Mol. Psychiatry. 2021 doi: 10.1038/s41380-021-01257-0.
    1. Saito T., Matsuba Y., Mihira N., Takano J., Nilsson P., Itohara S., Iwata N., Saido T.C. Single App knock-in mouse models of Alzheimer’s disease. Nat. Neurosci. 2014;17:661–663. doi: 10.1038/nn.3697.
    1. Chapman P.F., White G.L., Jones M.W., Cooper-Blacketer D., Marshall V.J., Irizarry M., Younkin L., Good M.A., Bliss T.V., Hyman B.T., et al. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat. Neurosci. 1999;2:271–276. doi: 10.1038/6374.
    1. Montgomery K.S., Edwards G., 3rd, Levites Y., Kumar A., Myers C.E., Gluck M.A., Setlow B., Bizon J.L. Deficits in hippocampal-dependent transfer generalization learning accompany synaptic dysfunction in a mouse model of amyloidosis. Hippocampus. 2016;26:455–471. doi: 10.1002/hipo.22535.
    1. Crouzin N., Baranger K., Cavalier M., Marchalant Y., Cohen-Solal C., Roman F.S., Khrestchatisky M., Rivera S., Féron F., Vignes M. Area-specific alterations of synaptic plasticity in the 5XFAD mouse model of Alzheimer’s disease: Dissociation between somatosensory cortex and hippocampus. PLoS ONE. 2013;8:e74667. doi: 10.1371/journal.pone.0074667.
    1. Oddo S., Caccamo A., Shepherd J.D., Murphy M.P., Golde T.E., Kayed R., Metherate R., Mattson M.P., Akbari Y., LaFerla F.M. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron. 2003;39:409–421. doi: 10.1016/S0896-6273(03)00434-3.
    1. Dietrich K., Bouter Y., Müller M., Bayer T.A. Synaptic Alterations in Mouse Models for Alzheimer Disease-A Special Focus on N-Truncated Abeta 4-42. Molecules. 2018;23:718. doi: 10.3390/molecules23040718.
    1. Apostolova L.G., Green A.E., Babakchanian S., Hwang K.S., Chou Y.Y., Toga A.W., Thompson P.M. Hippocampal atrophy and ventricular enlargement in normal aging, mild cognitive impairment (MCI), and Alzheimer Disease. Alzheimer Dis. Assoc. Disord. 2012;26:17–27. doi: 10.1097/WAD.0b013e3182163b62.
    1. Norfray J.F., Provenzale J.M. Alzheimer’s disease: Neuropathologic findings and recent advances in imaging. AJR Am. J. Roentgenol. 2004;182:3–13. doi: 10.2214/ajr.182.1.1820003.
    1. Wang Q., Xu Z., Tang J., Sun J., Gao J., Wu T., Xiao M. Voluntary exercise counteracts Aβ25-35-induced memory impairment in mice. Behav. Brain Res. 2013;256:618–625. doi: 10.1016/j.bbr.2013.09.024.
    1. Azimi M., Gharakhanlou R., Naghdi N., Khodadadi D., Heysieattalab S. Moderate treadmill exercise ameliorates amyloid-β-induced learning and memory impairment, possibly via increasing AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNF pathway. Peptides. 2018;102:78–88. doi: 10.1016/j.peptides.2017.12.027.
    1. Giménez-Llort L., García Y., Buccieri K., Revilla S., Suñol C., Cristofol R., Sanfeliu C. Gender-Specific Neuroimmunoendocrine Response to Treadmill Exercise in 3xTg-AD Mice. Int. J. Alzheimers Dis. 2010;2010:128354. doi: 10.4061/2010/128354.
    1. Alkadhi K.A., Dao A.T. Exercise decreases BACE and APP levels in the hippocampus of a rat model of Alzheimer’s disease. Mol. Cell. Neurosci. 2018;86:25–29. doi: 10.1016/j.mcn.2017.11.008.
    1. George E.K., Reddy P.H. Can Healthy Diets, Regular Exercise, and Better Lifestyle Delay the Progression of Dementia in Elderly Individuals? J. Alzheimers Dis. JAD. 2019;72:S37–S58. doi: 10.3233/JAD-190232.
    1. De Sousa R.A.L., Rodrigues C.M., Mendes B.F., Improta-Caria A.C., Peixoto M.F.D., Cassilhas R.C. Physical exercise protocols in animal models of Alzheimer’s disease: A systematic review. Metab. Brain Dis. 2021;36:85–95. doi: 10.1007/s11011-020-00633-z.
    1. Koo J.H., Kang E.B., Oh Y.S., Yang D.S., Cho J.Y. Treadmill exercise decreases amyloid-β burden possibly via activation of SIRT-1 signaling in a mouse model of Alzheimer’s disease. Exp. Neurol. 2017;288:142–152. doi: 10.1016/j.expneurol.2016.11.014.
    1. Lourenco M.V., Frozza R.L., de Freitas G.B., Zhang H., Kincheski G.C., Ribeiro F.C., Gonçalves R.A., Clarke J.R., Beckman D., Staniszewski A., et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat. Med. 2019;25:165–175. doi: 10.1038/s41591-018-0275-4.
    1. Sousa R.A.L., Lima N.S., Amorim F.T., Gripp F., Magalhães C., Pinto S.H., Dias-Peixoto M.F., Monteiro-Junior R.S., Bourbeau K., Cassilhas R.C. Endurance and high-intensity interval training improve the levels of anxiety and quality of life in overweight men. Rev. Assoc. Med. Bras. (1992) 2021;67:1177–1181. doi: 10.1590/1806-9282.20210608.
    1. Fernandes J., Arida R.M., Gomez-Pinilla F. Physical exercise as an epigenetic modulator of brain plasticity and cognition. Neurosci. Biobehav. Rev. 2017;80:443–456. doi: 10.1016/j.neubiorev.2017.06.012.
    1. Li Y., Zhao L., Gu B., Cai J., Lv Y., Yu L. Aerobic exercise regulates Rho/cofilin pathways to rescue synaptic loss in aged rats. PLoS ONE. 2017;12:e0171491. doi: 10.1371/journal.pone.0171491.
    1. Choi D.H., Lee K.H., Lee J. Effect of exercise-induced neurogenesis on cognitive function deficit in a rat model of vascular dementia. Mol. Med. Rep. 2016;13:2981–2990. doi: 10.3892/mmr.2016.4891.
    1. Cao L.M., Dong Z.Q., Li Q., Chen X. Treadmill training improves neurological deficits and suppresses neuronal apoptosis in cerebral ischemic stroke rats. Neural Regen. Res. 2019;14:1387–1393. doi: 10.4103/1673-5374.253523.
    1. Preston A.R., Eichenbaum H. Interplay of hippocampus and prefrontal cortex in memory. Curr. Biol. CB. 2013;23:R764–R773. doi: 10.1016/j.cub.2013.05.041.
    1. Andrade-Talavera Y., Rodríguez-Moreno A. Synaptic Plasticity and Oscillations in Alzheimer’s Disease: A Complex Picture of a Multifaceted Disease. Front. Mol. Neurosci. 2021;14:696476. doi: 10.3389/fnmol.2021.696476.
    1. Marrone D.F., Petit T.L. The role of synaptic morphology in neural plasticity: Structural interactions underlying synaptic power. Brain Res. Brain Res. Rev. 2002;38:291–308. doi: 10.1016/S0165-0173(01)00147-3.
    1. Savtchenko L.P., Rusakov D.A. The optimal height of the synaptic cleft. Proc. Natl. Acad. Sci. USA. 2007;104:1823–1828. doi: 10.1073/pnas.0606636104.
    1. Wahl L.M., Pouzat C., Stratford K.J. Monte Carlo simulation of fast excitatory synaptic transmission at a hippocampal synapse. J. Neurophysiol. 1996;75:597–608. doi: 10.1152/jn.1996.75.2.597.
    1. Coba M.P., Pocklington A.J., Collins M.O., Kopanitsa M.V., Uren R.T., Swamy S., Croning M.D., Choudhary J.S., Grant S.G. Neurotransmitters drive combinatorial multistate postsynaptic density networks. Sci. Signal. 2009;2:ra19. doi: 10.1126/scisignal.2000102.
    1. Huang F.L., Huang K.P., Wu J., Boucheron C. Environmental enrichment enhances neurogranin expression and hippocampal learning and memory but fails to rescue the impairments of neurogranin null mutant mice. J. Neurosci. Off. J. Soc. Neurosci. 2006;26:6230–6237. doi: 10.1523/JNEUROSCI.1182-06.2006.
    1. Ren W.J., Liu Y., Zhou L.J., Li W., Zhong Y., Pang R.P., Xin W.J., Wei X.H., Wang J., Zhu H.Q., et al. Peripheral nerve injury leads to working memory deficits and dysfunction of the hippocampus by upregulation of TNF-α in rodents. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 2011;36:979–992. doi: 10.1038/npp.2010.236.
    1. Kim K.M., Son K., Palmore G.T. Neuron Image Analyzer: Automated and Accurate Extraction of Neuronal Data from Low Quality Images. Sci. Rep. 2015;5:17062. doi: 10.1038/srep17062.
    1. Alcantara-Gonzalez F., Juarez I., Solis O., Martinez-Tellez I., Camacho-Abrego I., Masliah E., Mena R., Flores G. Enhanced dendritic spine number of neurons of the prefrontal cortex, hippocampus, and nucleus accumbens in old rats after chronic donepezil administration. Synapse. 2010;64:786–793. doi: 10.1002/syn.20787.
    1. Sánchez F., Gómez-Villalobos Mde J., Juarez I., Quevedo L., Flores G. Dendritic morphology of neurons in medial prefrontal cortex, hippocampus, and nucleus accumbens in adult SH rats. Synapse. 2011;65:198–206. doi: 10.1002/syn.20837.
    1. Sholl D.A. Dendritic organization in the neurons of the visual and motor cortices of the cat. J. Anat. 1953;87:387–406.
    1. Ma X.M., Huang J., Wang Y., Eipper B.A., Mains R.E. Kalirin, a multifunctional Rho guanine nucleotide exchange factor, is necessary for maintenance of hippocampal pyramidal neuron dendrites and dendritic spines. J. Neurosci. Off. J. Soc. Neurosci. 2003;23:10593–10603. doi: 10.1523/JNEUROSCI.23-33-10593.2003.
    1. Qiao H., Li M.X., Xu C., Chen H.B., An S.C., Ma X.M. Dendritic Spines in Depression: What We Learned from Animal Models. Neural Plast. 2016;2016:8056370. doi: 10.1155/2016/8056370.
    1. Park J., Trinh V.N., Sears-Kraxberger I., Li K.W., Steward O., Luo Z.D. Synaptic ultrastructure changes in trigeminocervical complex posttrigeminal nerve injury. J. Comp. Neurol. 2016;524:309–322. doi: 10.1002/cne.23844.
    1. Güldner F.H. Sexual dimorphisms of axo-spine synapses and postsynaptic density material in the suprachiasmatic nucleus of the rat. Neurosci. Lett. 1982;28:145–150. doi: 10.1016/0304-3940(82)90143-4.
    1. Orduz D., Boom A., Gall D., Brion J.P., Schiffmann S.N., Schwaller B. Subcellular structural plasticity caused by the absence of the fast Ca(2+) buffer calbindin D-28k in recurrent collaterals of cerebellar Purkinje neurons. Front. Cell. Neurosci. 2014;8:364. doi: 10.3389/fncel.2014.00364.
    1. Jones D.G., Devon R.M. An ultrastructural study into the effects of pentobarbitone on synaptic organization. Brain Res. 1978;147:47–63. doi: 10.1016/0006-8993(78)90771-0.
    1. Cooke C.T., Nolan T.M., Dyson S.E., Jones D.G. Pentobarbital-induced configurational changes at the synapse. Brain Res. 1974;76:330–335. doi: 10.1016/0006-8993(74)90464-8.
    1. Ehrlich I., Klein M., Rumpel S., Malinow R. PSD-95 is required for activity-driven synapse stabilization. Proc. Natl. Acad. Sci. USA. 2007;104:4176–4181. doi: 10.1073/pnas.0609307104.
    1. Kokotos A.C., Harper C.B., Marland J.R.K., Smillie K.J., Cousin M.A., Gordon S.L. Synaptophysin sustains presynaptic performance by preserving vesicular synaptobrevin-II levels. J. Neurochem. 2019;151:28–37. doi: 10.1111/jnc.14797.
    1. Berry K.P., Nedivi E. Spine Dynamics: Are They All the Same? Neuron. 2017;96:43–55. doi: 10.1016/j.neuron.2017.08.008.
    1. Bourne J., Harris K.M. Do thin spines learn to be mushroom spines that remember? Curr. Opin. Neurobiol. 2007;17:381–386. doi: 10.1016/j.conb.2007.04.009.
    1. Holtmaat A.J., Trachtenberg J.T., Wilbrecht L., Shepherd G.M., Zhang X., Knott G.W., Svoboda K. Transient and persistent dendritic spines in the neocortex in vivo. Neuron. 2005;45:279–291. doi: 10.1016/j.neuron.2005.01.003.
    1. Zuo Y., Lin A., Chang P., Gan W.B. Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron. 2005;46:181–189. doi: 10.1016/j.neuron.2005.04.001.
    1. Harris K.M., Jensen F.E., Tsao B. Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: Implications for the maturation of synaptic physiology and long-term potentiation. J. Neurosci. Off. J. Soc. Neurosci. 1992;12:2685–2705. doi: 10.1523/JNEUROSCI.12-07-02685.1992.
    1. Bello-Medina P.C., Prado-Alcalá R.A., Rivas-Arancibia S. Effect of Ozone Exposure on Dendritic Spines of CA1 Pyramidal Neurons of the Dorsal Hippocampus and on Object-place Recognition Memory in Rats. Neuroscience. 2019;402:1–10. doi: 10.1016/j.neuroscience.2019.01.018.
    1. Brown M.F., Farley R.F., Lorek E.J. Remembrance of places you passed: Social spatial working memory in rats. J. Exp. Psychol. Anim. Behav. Process. 2007;33:213–224. doi: 10.1037/0097-7403.33.3.213.
    1. Cowan N. What are the differences between long-term, short-term, and working memory? Prog. Brain Res. 2008;169:323–338. doi: 10.1016/s0079-6123(07)00020-9.
    1. Bizon J.L., Foster T.C., Alexander G.E., Glisky E.L. Characterizing cognitive aging of working memory and executive function in animal models. Front. Aging Neurosci. 2012;4:19. doi: 10.3389/fnagi.2012.00019.
    1. Kim D., Cho J., Kang H. Protective effect of exercise training against the progression of Alzheimer’s disease in 3xTg-AD mice. Behav. Brain Res. 2019;374:112105. doi: 10.1016/j.bbr.2019.112105.
    1. Cho J., Shin M.K., Kim D., Lee I., Kim S., Kang H. Treadmill Running Reverses Cognitive Declines due to Alzheimer Disease. Med. Sci. Sports Exerc. 2015;47:1814–1824. doi: 10.1249/MSS.0000000000000612.
    1. Bromley-Brits K., Deng Y., Song W. Morris water maze test for learning and memory deficits in Alzheimer’s disease model mice. J. Vis. Exp. JoVE. 2011;53:2920. doi: 10.3791/2920.
    1. Bailey C.H., Kandel E.R., Harris K.M. Structural Components of Synaptic Plasticity and Memory Consolidation. Cold Spring Harb. Perspect. Biol. 2015;7:a021758. doi: 10.1101/cshperspect.a021758.
    1. Weyhersmüller A., Hallermann S., Wagner N., Eilers J. Rapid active zone remodeling during synaptic plasticity. J. Neurosci. Off. J. Soc. Neurosci. 2011;31:6041–6052. doi: 10.1523/JNEUROSCI.6698-10.2011.
    1. Zeng M., Chen X., Guan D., Xu J., Wu H., Tong P., Zhang M. Reconstituted Postsynaptic Density as a Molecular Platform for Understanding Synapse Formation and Plasticity. Cell. 2018;174:1172–1187.e16. doi: 10.1016/j.cell.2018.06.047.
    1. Kolos Y.A., Grigoriyev I.P., Korzhevskyi D.E. A synaptic marker synaptophysin. Morfologiia. 2015;147:78–82.
    1. Jeanneret V., Ospina J.P., Diaz A., Manrique L.G., Merino P., Gutierrez L., Torre E., Wu F., Cheng L., Yepes M. Tissue-type plasminogen activator protects the postsynaptic density in the ischemic brain. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2018;38:1896–1910. doi: 10.1177/0271678X18764495.
    1. Revilla S., Suñol C., García-Mesa Y., Giménez-Llort L., Sanfeliu C., Cristòfol R. Physical exercise improves synaptic dysfunction and recovers the loss of survival factors in 3xTg-AD mouse brain. Neuropharmacology. 2014;81:55–63. doi: 10.1016/j.neuropharm.2014.01.037.
    1. Tsai J., Grutzendler J., Duff K., Gan W.B. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat. Neurosci. 2004;7:1181–1183. doi: 10.1038/nn1335.
    1. Zhang Y., Xiao Z., He Z., Chen J., Wang X., Jiang L. Dendritic complexity change in the triple transgenic mouse model of Alzheimer’s disease. PeerJ. 2020;8:e8178. doi: 10.7717/peerj.8178.
    1. Debanne D., Campanac E., Bialowas A., Carlier E., Alcaraz G. Axon physiology. Physiol. Rev. 2011;91:555–602. doi: 10.1152/physrev.00048.2009.
    1. Nimchinsky E.A., Sabatini B.L., Svoboda K. Structure and function of dendritic spines. Annu. Rev. Physiol. 2002;64:313–353. doi: 10.1146/annurev.physiol.64.081501.160008.
    1. Alobuia W.M., Xia W., Vohra B.P. Axon degeneration is key component of neuronal death in amyloid-β toxicity. Neurochem. Int. 2013;63:782–789. doi: 10.1016/j.neuint.2013.08.013.
    1. Andrade-Talavera Y., Chen G., Kurudenkandy F.R., Johansson J., Fisahn A. Bri2 BRICHOS chaperone rescues impaired fast-spiking interneuron behavior and neuronal network dynamics in an AD mouse model in vitro. Neurobiol. Dis. 2021;159:105514. doi: 10.1016/j.nbd.2021.105514.
    1. Pchitskaya E., Bezprozvanny I. Dendritic Spines Shape Analysis-Classification or Clusterization? Perspective. Front. Synaptic Neurosci. 2020;12:31. doi: 10.3389/fnsyn.2020.00031.
    1. Kasai H., Fukuda M., Watanabe S., Hayashi-Takagi A., Noguchi J. Structural dynamics of dendritic spines in memory and cognition. Trends Neurosci. 2010;33:121–129. doi: 10.1016/j.tins.2010.01.001.
    1. Kandimalla R., Manczak M., Yin X., Wang R., Reddy P.H. Hippocampal phosphorylated tau induced cognitive decline, dendritic spine loss and mitochondrial abnormalities in a mouse model of Alzheimer’s disease. Hum. Mol. Genet. 2018;27:30–40. doi: 10.1093/hmg/ddx381.
    1. Parajuli L.K., Wako K., Maruo S., Kakuta S., Taguchi T., Ikuno M., Yamakado H., Takahashi R., Koike M. Developmental Changes in Dendritic Spine Morphology in the Striatum and Their Alteration in an A53T α-Synuclein Transgenic Mouse Model of Parkinson’s Disease. eNeuro. 2020;7:ENEURO.0072-20.2020. doi: 10.1523/ENEURO.0072-20.2020.
    1. Freund R.K., Gibson E.S., Potter H., Dell’Acqua M.L. Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss. Mol. Pharmacol. 2016;89:552–559. doi: 10.1124/mol.115.103085.
    1. Frankfurt M., Luine V. The evolving role of dendritic spines and memory: Interaction(s) with estradiol. Horm. Behav. 2015;74:28–36. doi: 10.1016/j.yhbeh.2015.05.004.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться