{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T16:29:54Z","timestamp":1793636994153,"version":"4.5.1"},"reference-count":138,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T00:00:00Z","timestamp":1677456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent evidence has supported the hypothesis that amyotrophic lateral sclerosis (ALS) is a multi-step disease, as the onset of symptoms occurs after sequential exposure to a defined number of risk factors. Despite the lack of precise identification of these disease determinants, it is known that genetic mutations may contribute to one or more of the steps leading to ALS onset, the remaining being linked to environmental factors and lifestyle. It also appears evident that compensatory plastic changes taking place at all levels of the nervous system during ALS etiopathogenesis may likely counteract the functional effects of neurodegeneration and affect the timing of disease onset and progression. Functional and structural events of synaptic plasticity probably represent the main mechanisms underlying this adaptive capability, causing a significant, although partial and transient, resiliency of the nervous system affected by a neurodegenerative disease. On the other hand, the failure of synaptic functions and plasticity may be part of the pathological process. The aim of this review was to summarize what it is known today about the controversial involvement of synapses in ALS etiopathogenesis, and an analysis of the literature, although not exhaustive, confirmed that synaptic dysfunction is an early pathogenetic process in ALS. Moreover, it appears that adequate modulation of structural and functional synaptic plasticity may likely support function sparing and delay disease progression.<\/jats:p>","DOI":"10.3390\/ijms24054613","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T04:05:40Z","timestamp":1677470740000},"page":"4613","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Synaptic Dysfunction and Plasticity in Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8067-697X","authenticated-orcid":false,"given":"Rosario","family":"Gulino","sequence":"first","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.14336\/AD.2013.0400295","article-title":"Amyotrophic lateral sclerosis: An update for 2013 clinical features, pathophysiology, management and therapeutic trials","volume":"4","author":"Gordon","year":"2013","journal-title":"Aging Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3109\/17482960802566824","article-title":"Prognostic factors in ALS: A critical review","volume":"10","author":"Logroscino","year":"2009","journal-title":"Amyotroph. Lateral Scler."},{"key":"ref_3","first-page":"5673","article-title":"Recent updates on the genetics of amyotrophic lateral sclerosis and frontotemporal dementia","volume":"59","author":"Kirola","year":"2022","journal-title":"Mol. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1126\/science.1134108","article-title":"Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"314","author":"Neumann","year":"2006","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","article-title":"A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD","volume":"72","author":"Renton","year":"2011","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3233\/BPL-140001","article-title":"Synaptic failure: Focus in an integrative view of ALS","volume":"1","author":"Casas","year":"2016","journal-title":"Brain Plast."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/S1474-4422(13)70036-X","article-title":"Controversies and priorities in amyotrophic lateral sclerosis","volume":"12","author":"Turner","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/mus.10191","article-title":"Inflammatory processes in amyotrophic lateral sclerosis","volume":"26","author":"McGeer","year":"2002","journal-title":"Muscle Nerve"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.cell.2010.02.016","article-title":"Mechanisms underlying inflammation in neurodegeneration","volume":"140","author":"Glass","year":"2010","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17085","DOI":"10.1038\/nrdp.2017.85","article-title":"Amyotrophic lateral sclerosis","volume":"3","author":"Hardiman","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"134621","DOI":"10.1016\/j.neulet.2019.134621","article-title":"Toxicity in ALS: TDP-43 modifiers and C9orf72","volume":"716","author":"Wang","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"dmm037424","DOI":"10.1242\/dmm.037424","article-title":"Transgenic and physiological mouse models give insights into different aspects of amyotrophic lateral sclerosis","volume":"12","author":"Maduro","year":"2019","journal-title":"Dis. Model. Mech."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5.67.1","DOI":"10.1002\/0471141755.ph0567s69","article-title":"Rodent models of amyotrophic lateral sclerosis","volume":"69","author":"Philips","year":"2015","journal-title":"Curr. Protoc. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1016\/S1474-4422(14)70219-4","article-title":"Analysis of amyotrophic lateral sclerosis as a multistep process: A population-based modelling study","volume":"13","author":"Calvo","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e635","DOI":"10.1212\/WNL.0000000000005996","article-title":"The multistep hypothesis of ALS revisited: The role of genetic mutations","volume":"91","author":"Mazzini","year":"2018","journal-title":"Neurology"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ciuro, M., Sangiorgio, M., Leanza, G., and Gulino, R. (2022). A meta-analysis study of SOD1-mutant mouse models of ALS to analyse the determinants of disease onset and progression. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010216"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nrneurol.2016.182","article-title":"Gene discovery in amyotrophic lateral sclerosis: Implications for clinical management","volume":"13","author":"Veldink","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1080\/21678421.2020.1779298","article-title":"Focus on the heterogeneity of amyotrophic lateral sclerosis","volume":"21","author":"Bendotti","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1002\/mus.21936","article-title":"Onset and spreading patterns of upper and lower motor neuron symptoms in amyotrophic lateral sclerosis","volume":"43","author":"Kollewe","year":"2011","journal-title":"Muscle Nerve"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1136\/jnnp-2011-301826","article-title":"Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation?","volume":"83","author":"Kanouchi","year":"2012","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1212\/WNL.0b013e3181b6bbbd","article-title":"ALS motor phenotype heterogeneity, focality, and spread","volume":"73","author":"Ravits","year":"2009","journal-title":"Neurology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1038\/81453","article-title":"Synaptic plasticity. taming the beast","volume":"3","author":"Abbott","year":"2000","journal-title":"Nat. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.conb.2018.08.010","article-title":"Homeostatic synaptic plasticity as a metaplasticity mechanism\u2014A molecular and cellular perspective","volume":"54","author":"Li","year":"2019","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neuron.2013.12.025","article-title":"Sleep and the price of plasticity: From synaptic and cellular homeostasis to memory consolidation and integration","volume":"81","author":"Tononi","year":"2014","journal-title":"Neuron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"a005736","DOI":"10.1101\/cshperspect.a005736","article-title":"Homeostatic synaptic plasticity: Local and global mechanisms for stabilizing neuronal function","volume":"4","author":"Turrigiano","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-319-62817-2_1","article-title":"What is neural plasticity?","volume":"1015","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/B978-0-444-63327-9.00003-5","article-title":"Cortical plasticity, excitatory-inhibitory balance, and sensory perception","volume":"207","author":"Carcea","year":"2013","journal-title":"Prog. Brain Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1146\/annurev.neuro.28.061604.135751","article-title":"Homeostatic control of neural activity: From phenomenology to molecular design","volume":"29","author":"Davis","year":"2006","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1146\/annurev-neuro-060909-153238","article-title":"Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement","volume":"34","author":"Turrigiano","year":"2011","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3389\/fnana.2016.00075","article-title":"Opposing effects of neuronal activity on structural plasticity","volume":"10","author":"Fauth","year":"2016","journal-title":"Front. Neuroanat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1113\/JP275498","article-title":"The vulnerability of spinal motoneurons and soma size plasticity in a mouse model of amyotrophic lateral sclerosis","volume":"596","author":"Dukkipati","year":"2018","journal-title":"J. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.jphysparis.2005.12.014","article-title":"Early abnormalities in transgenic mouse models of amyotrophic lateral sclerosis","volume":"99","author":"Durand","year":"2006","journal-title":"J. Physiol. Paris"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/cne.24751","article-title":"Compensatory changes in degenerating spinal motoneurons sustain functional sparing in the SOD1-G93A mouse model of amyotrophic lateral sclerosis","volume":"528","author":"Giusto","year":"2020","journal-title":"J. Comp. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Gulino, R., Vicario, N., Giunta, M.A.S., Spoto, G., Calabrese, G., Vecchio, M., Gulisano, M., Leanza, G., and Parenti, R. (2019). Neuromuscular plasticity in a mouse model of spinal motoneuronal loss. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061500"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"55","DOI":"10.2174\/1871527314666150116115414","article-title":"TDP-43 as a modulator of synaptic plasticity in a mouse model of spinal motoneuron degeneration","volume":"14","author":"Gulino","year":"2015","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1111\/j.1460-9568.2010.07170.x","article-title":"Expression of cell-fate determinants and plastic changes after neurotoxic lesion of adult mice spinal cord by cholera toxin-B saporin","volume":"31","author":"Gulino","year":"2010","journal-title":"Eur. J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/s41419-021-03907-1","article-title":"Clobetasol promotes neuromuscular plasticity in mice after motoneuronal loss via sonic hedgehog signaling, immunomodulation and metabolic rebalancing","volume":"12","author":"Vicario","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"782768","DOI":"10.3389\/fncel.2021.782768","article-title":"Friend or foe? The varied faces of homeostatic synaptic plasticity in neurodegenerative disease","volume":"15","author":"Taylor","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1950007","DOI":"10.1142\/S0129065719500072","article-title":"Strong-weak pruning for brain network identification in connectome-wide neuroimaging: Application to amyotrophic lateral sclerosis disease stage characterization","volume":"29","author":"Serra","year":"2019","journal-title":"Int. J. Neural. Syst."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13024-021-00433-8","article-title":"Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction","volume":"16","author":"Perkins","year":"2021","journal-title":"Mol. Neurodegener."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.neuropharm.2018.09.021","article-title":"Riluzole attenuates the efficacy of glutamatergic transmission by interfering with the size of the readily releasable neurotransmitter pool","volume":"143","author":"Lazarevic","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1093\/cercor\/bhr002","article-title":"Sensorimotor functional connectivity changes in amyotrophic lateral sclerosis","volume":"21","author":"Agosta","year":"2011","journal-title":"Cereb. Cortex"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1002\/hbm.22070","article-title":"Brain plasticity in the motor network is correlated with disease progression in amyotrophic lateral sclerosis","volume":"34","author":"Poujois","year":"2013","journal-title":"Hum. Brain Mapp."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s11682-017-9738-3","article-title":"Functional reorganization during cognitive function tasks in patients with amyotrophic lateral sclerosis","volume":"12","author":"Keller","year":"2018","journal-title":"Brain Imaging Behav."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s00221-006-0352-7","article-title":"Subcortical reorganization in amyotrophic lateral sclerosis","volume":"172","author":"Konrad","year":"2006","journal-title":"Exp. Brain Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1177\/1545968307300698","article-title":"Cortical plasticity in amyotrophic lateral sclerosis: Motor imagery and function","volume":"21","author":"Diekmann","year":"2007","journal-title":"Neurorehabil. Neural Repair"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1002\/hbm.21064","article-title":"Functional neuroimaging at different disease stages reveals distinct phases of neuroplastic changes in amyotrophic lateral sclerosis","volume":"32","author":"Mohammadi","year":"2011","journal-title":"Hum. Brain Mapp."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1093\/cercor\/bhq152","article-title":"Postsynaptic alteration of NR2A subunit and defective autophosphorylation of alphaCaMKII at threonine-286 contribute to abnormal plasticity and morphology of upper motor neurons in presymptomatic SOD1G93A mice, a murine model for amyotrophic lateral sclerosis","volume":"21","author":"Spalloni","year":"2011","journal-title":"Cereb. Cortex"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"496","DOI":"10.3389\/fncel.2015.00496","article-title":"Super-resolution microscopy reveals presynaptic localization of the ALS\/FTD related protein FUS in hippocampal neurons","volume":"9","author":"Schoen","year":"2016","journal-title":"Front. Cell. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s40478-020-01111-4","article-title":"Dysfunction in nonsense-mediated decay, protein homeostasis, mitochondrial function, and brain connectivity in ALS-FUS mice with cognitive deficits","volume":"9","author":"Ho","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.neuron.2018.09.044","article-title":"ALS\/FTD-linked mutation in FUS suppresses intra-axonal protein synthesis and drives disease without nuclear loss-of-function of FUS","volume":"100","author":"Tadokoro","year":"2018","journal-title":"Neuron"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3027","DOI":"10.1038\/s41467-021-23188-8","article-title":"Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS","volume":"12","author":"Sahadevan","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9037","DOI":"10.1523\/JNEUROSCI.0811-17.2017","article-title":"Changes in the excitability of neocortical neurons in a mouse model of amyotrophic lateral sclerosis are not specific to corticospinal neurons and are modulated by advancing disease","volume":"37","author":"Kim","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"330","DOI":"10.7150\/thno.51004","article-title":"TDP-43 proteinopathy impairs mRNP granule mediated postsynaptic translation and mRNA metabolism","volume":"11","author":"Wong","year":"2021","journal-title":"Theranostics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2962","DOI":"10.1007\/s12035-022-02742-5","article-title":"Estrogen enhances dendrite spine function and recovers deficits in neuroplasticity in the prpTDP-43A315T mouse model of amyotrophic lateral sclerosis","volume":"59","author":"Handley","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s40478-022-01386-9","article-title":"Modulation of synaptic plasticity, motor unit physiology, and TDP-43 pathology by CHCHD10","volume":"10","author":"Liu","year":"2022","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1084\/jem.20092164","article-title":"Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U","volume":"207","author":"Tsai","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s40478-019-0674-x","article-title":"Transcriptomopathies of pre- and post-symptomatic frontotemporal dementia-like mice with TDP-43 depletion in forebrain neurons","volume":"7","author":"Wu","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1126\/science.abl5163","article-title":"Impact of neurodegenerative diseases on human adult hippocampal neurogenesis","volume":"374","author":"Trinchero","year":"2021","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/s40478-020-01030-4","article-title":"Deregulated expression of a longevity gene, Klotho, in the C9orf72 deletion mice with impaired synaptic plasticity and adult hippocampal neurogenesis","volume":"8","author":"Ho","year":"2020","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s00401-022-02470-z","article-title":"An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS\/FTD","volume":"144","author":"Bauer","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s40478-019-0812-5","article-title":"Synaptic localization of C9orf72 regulates post-synaptic glutamate receptor 1 levels","volume":"7","author":"Xiao","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.neuron.2018.04.032","article-title":"RNP-granule assembly via Ataxin-2 disordered domains is required for long-term memory and neurodegeneration","volume":"98","author":"Bakthavachalu","year":"2018","journal-title":"Neuron"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3710","DOI":"10.1093\/brain\/awab333","article-title":"Defective cyclophilin A induces TDP-43 proteinopathy: Implications for amyotrophic lateral sclerosis and frontotemporal dementia","volume":"144","author":"Pasetto","year":"2021","journal-title":"Brain"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"104499","DOI":"10.1016\/j.nbd.2019.104499","article-title":"Neuronal TDP-43 depletion affects activity-dependent plasticity","volume":"130","author":"Koza","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.expneurol.2005.10.014","article-title":"Molecular and synaptic changes in the hippocampus underlying superior spatial abilities in pre-symptomatic G93A+\/+ mice overexpressing the human Cu\/Zn superoxide dismutase (Gly93 --> ALA) mutation","volume":"197","author":"Spalloni","year":"2006","journal-title":"Exp. Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.mcn.2018.03.010","article-title":"Deletion of the endogenous TrkB.T1 receptor isoform restores the number of hippocampal CA1 parvalbumin-positive neurons and rescues long-term potentiation in pre-symptomatic mSOD1(G93A) ALS mice","volume":"89","author":"Quarta","year":"2018","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"108106","DOI":"10.1016\/j.neuropharm.2020.108106","article-title":"Hippocampal synaptic dysfunction in the SOD1G93A mouse model of Amyotrophic Lateral Sclerosis: Reversal by adenosine A2AR blockade","volume":"171","author":"Rei","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1016\/j.clinph.2020.09.021","article-title":"Amyotrophic lateral sclerosis weakens spinal recurrent inhibition and post-activation depression","volume":"131","author":"Topkara","year":"2020","journal-title":"Clin. Neurophysiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/BF00293397","article-title":"Synapse loss in anterior horn neurons in amyotrophic lateral sclerosis","volume":"88","author":"Sasaki","year":"1994","journal-title":"Acta Neuropathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1007\/BF01271192","article-title":"Synaptophysin in spinal anterior horn in aging and ALS: An immunohistological study","volume":"103","author":"Moral","year":"1996","journal-title":"J. Neural Transm."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.neuroscience.2017.08.041","article-title":"Hyperexcitability in synaptic and firing activities of spinal motoneurons in an adult mouse model of amyotrophic lateral sclerosis","volume":"362","author":"Jiang","year":"2017","journal-title":"Neuroscience"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.neuroscience.2012.09.031","article-title":"Gender-specific perturbations in modulatory inputs to motoneurons in a mouse model of amyotrophic lateral sclerosis","volume":"226","author":"Herron","year":"2012","journal-title":"Neuroscience"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1111\/j.1460-9568.2008.06602.x","article-title":"Increase in presynaptic territory of C-terminals on lumbar motoneurons of G93A SOD1 mice during disease progression","volume":"29","author":"Pullen","year":"2009","journal-title":"Eur. J. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s40478-016-0286-7","article-title":"Neuregulin 1 confers neuroprotection in SOD1-linked amyotrophic lateral sclerosis mice via restoration of C-boutons of spinal motor neurons","volume":"4","author":"Lasiene","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.neuroscience.2012.01.046","article-title":"Postnatal dendritic development in lumbar motoneurons in mutant superoxide dismutase 1 mouse model of amyotrophic lateral sclerosis","volume":"209","author":"Filipchuk","year":"2012","journal-title":"Neuroscience"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Brockington, A., Heath, P.R., Holden, H., Kasher, P., Bender, F.L.P., Claes, F., Lambrechts, D., Sendtner, M., Carmeliet, P., and Shaw, P.J. (2010). Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGFdelta\/delta mouse model of amyotrophic lateral sclerosis. BMC Genom., 11.","DOI":"10.1186\/1471-2164-11-203"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1179\/174313206X152519","article-title":"Increased number and differentiation of neural precursor cells in the brainstem of superoxide dismutase 1(G93A) (G1H) transgenic mouse model of amyotrophic lateral sclerosis","volume":"29","author":"Juan","year":"2007","journal-title":"Neurol. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.neures.2012.04.010","article-title":"Involvement of brain-derived neurotrophic factor and sonic hedgehog in the spinal cord plasticity after neurotoxic partial removal of lumbar motoneurons","volume":"73","author":"Gulino","year":"2012","journal-title":"Neurosci. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.jns.2013.06.029","article-title":"Noggin and Sonic hedgehog are involved in compensatory changes within the motoneuron-depleted mouse spinal cord","volume":"332","author":"Gulino","year":"2013","journal-title":"J. Neurol. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"654637","DOI":"10.1155\/2015\/654637","article-title":"Novel mechanisms of spinal cord plasticity in a mouse model of motoneuron disease","volume":"2015","author":"Gulino","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"103471","DOI":"10.1016\/j.resp.2020.103471","article-title":"5-HT2A\/B receptor expression in the phrenic motor nucleus in a rat model of ALS (SOD1G93A)","volume":"279","author":"Borkowski","year":"2020","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.expneurol.2015.08.011","article-title":"Acute intermittent hypoxia induced phrenic long-term facilitation despite increased SOD1 expression in a rat model of ALS","volume":"273","author":"Nichols","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1006\/exnr.2002.8011","article-title":"Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis","volume":"177","author":"Copray","year":"2002","journal-title":"Exp. Neurol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1523\/JNEUROSCI.20-07-02534.2000","article-title":"Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases","volume":"20","author":"Frey","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e16","DOI":"10.4081\/ni.2009.e16","article-title":"Early detachment of neuromuscular junction proteins in ALS mice with SODG93A mutation","volume":"1","author":"Narai","year":"2009","journal-title":"Neurol. Int."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1038\/nn1653","article-title":"Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF","volume":"9","author":"Pun","year":"2006","journal-title":"Nat. Neurosci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"8901","DOI":"10.1523\/JNEUROSCI.3090-16.2017","article-title":"Opposite synaptic alterations at the neuromuscular junction in an ALS mouse model: When motor units matter","volume":"37","author":"Tremblay","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.expneurol.2006.08.028","article-title":"Muscle-derived but not centrally derived transgene GDNF is neuroprotective in G93A-SOD1 mouse model of ALS","volume":"203","author":"Li","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.neuron.2020.04.009","article-title":"Presynaptic homeostasis opposes disease progression in mouse models of ALS-like degeneration: Evidence for homeostatic neuroprotection","volume":"107","author":"Orr","year":"2020","journal-title":"Neuron"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.nbd.2014.07.007","article-title":"Chronological requirements of TDP-43 function in synaptic organization and locomotive control","volume":"71","author":"Romano","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4153","DOI":"10.1093\/hmg\/ddx304","article-title":"Homeostatic plasticity can be induced and expressed to restore synaptic strength at neuromuscular junctions undergoing ALS-related degeneration","volume":"26","author":"Perry","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1000183","DOI":"10.3389\/fnmol.2022.1000183","article-title":"Synaptic dysfunction in ALS and FTD: Anatomical and molecular changes provide insights into mechanisms of disease","volume":"15","author":"Gelon","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1126\/science.1166066","article-title":"Mutations in the FUS\/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis","volume":"323","author":"Kwiatkowski","year":"2009","journal-title":"Science"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1126\/science.1165942","article-title":"Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6","volume":"323","author":"Vance","year":"2009","journal-title":"Science"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.brainres.2018.03.037","article-title":"FUS causes synaptic hyperexcitability in Drosophila dendritic arborization neurons","volume":"1693","author":"Machamer","year":"2018","journal-title":"Brain Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"fcac338","DOI":"10.1093\/braincomms\/fcac338","article-title":"Acetylcholine and noradrenaline differentially regulate hippocampus-dependent spatial learning and memory","volume":"5","author":"Gulino","year":"2022","journal-title":"Brain Commun."},{"key":"ref_98","unstructured":"Vardjan, N., and Zorec, R. (2017). Noradrenaline Signaling and Astroglia, Academic Press. [1st ed.]."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1002\/cne.24397","article-title":"Essential role of hippocampal noradrenaline in the regulation of spatial working memory and TDP-43 tissue pathology","volume":"526","author":"Pintus","year":"2018","journal-title":"J. Comp. Neurol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1111\/febs.15878","article-title":"Instructive roles of astrocytes in hippocampal synaptic plasticity: Neuronal activity-dependent regulatory mechanisms","volume":"289","author":"Wang","year":"2022","journal-title":"FEBS J."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Weerasinghe-Mudiyanselage, P.D.E., Ang, M.J., Kang, S., Kim, J.-S., and Moon, C. (2022). Structural plasticity of the hippocampus in neurodegenerative diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063349"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2419.e17","DOI":"10.1016\/j.neurobiolaging.2014.04.009","article-title":"Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion","volume":"35","author":"Pletnikova","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1093\/brain\/awr354","article-title":"Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p","volume":"135","author":"Hsiung","year":"2012","journal-title":"Brain"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"101828","DOI":"10.1016\/j.arr.2022.101828","article-title":"Insight into the role of adult hippocampal neurogenesis in aging and Alzheimer\u2019s disease","volume":"84","author":"Chen","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1038\/3305","article-title":"Neurogenesis in the adult human hippocampus","volume":"4","author":"Eriksson","year":"1998","journal-title":"Nat. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.1038\/npp.2015.85","article-title":"Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors","volume":"40","author":"Hill","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/S1474-4422(10)70195-2","article-title":"TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia","volume":"9","author":"Mackenzie","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"9220","DOI":"10.1007\/s12035-018-1059-z","article-title":"Characterization of the mitochondrial aerobic metabolism in the pre- and perisynaptic districts of the SOD1G93A mouse model of amyotrophic lateral sclerosis","volume":"55","author":"Ravera","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s00401-017-1708-8","article-title":"Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis","volume":"133","author":"Nijssen","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"8308","DOI":"10.1523\/JNEUROSCI.0719-10.2010","article-title":"Nerve growth factor regulates the firing patterns and synaptic composition of motoneurons","volume":"30","author":"Morcuende","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1069940","DOI":"10.3389\/fnmol.2022.1069940","article-title":"TrkB signaling is correlated with muscular fatigue resistance and less vulnerability to neurodegeneration","volume":"15","author":"Polishchuk","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1007\/s00429-020-02057-y","article-title":"Sources and lesion-induced changes of VEGF expression in brainstem motoneurons","volume":"225","author":"Pastor","year":"2020","journal-title":"Brain Struct. Funct."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"252","DOI":"10.3389\/fnins.2014.00252","article-title":"ALS as a distal axonopathy: Molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease","volume":"8","author":"Moloney","year":"2014","journal-title":"Front. Neurosci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.mcn.2006.03.002","article-title":"The expression of the chemorepellent Semaphorin 3A is selectively induced in terminal Schwann cells of a subset of neuromuscular synapses that display limited anatomical plasticity and enhanced vulnerability in motor neuron disease","volume":"32","author":"Vo","year":"2006","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1136\/jnnp.33.1.40","article-title":"Changes in motor innervation and cholinesterase localization induced by botulinum toxin in skeletal muscle of the mouse: Differences between fast and slow muscles","volume":"33","author":"Duchen","year":"1970","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0960-9822(02)70662-3","article-title":"Dynamic roles at the neuromuscular junction. Schwann cells","volume":"6","year":"1996","journal-title":"Curr. Biol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"a020503","DOI":"10.1101\/cshperspect.a020503","article-title":"Perisynaptic Schwann cells at the neuromuscular synapse: Adaptable, multitasking glial cells","volume":"7","author":"Ko","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/glia.24184","article-title":"Functional adaptation of glial cells at neuromuscular junctions in response to injury","volume":"70","author":"Provost","year":"2022","journal-title":"Glia"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1126\/science.7770776","article-title":"Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons","volume":"268","author":"Funakoshi","year":"1995","journal-title":"Science"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1152\/jn.1997.77.1.502","article-title":"Modulation of motoneuron excitability by brain-derived neurotrophic factor","volume":"77","author":"Gonzalez","year":"1997","journal-title":"J. Neurophysiol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1146\/annurev.neuro.22.1.295","article-title":"Neurotrophins and synaptic plasticity","volume":"22","author":"McAllister","year":"1999","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s40478-019-0802-7","article-title":"The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability","volume":"7","author":"Zelada","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1006\/exnr.2001.7753","article-title":"Overexpression of GDNF induces and maintains hyperinnervation of muscle fibers and multiple end-plate formation","volume":"171","author":"Zwick","year":"2001","journal-title":"Exp. Neurol."},{"key":"ref_124","first-page":"115","article-title":"Influence of the postsynaptic target on the functional properties of neurons in the adult mammalian central nervous system","volume":"7","author":"Pastor","year":"1996","journal-title":"Rev. Neurosci."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1002\/glia.24140","article-title":"Astrocyte-targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast-fatigable motor units in a mouse model of amyotrophic lateral sclerosis","volume":"70","author":"Rochat","year":"2022","journal-title":"Glia"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1242\/dmm.018606","article-title":"Identifying the primary site of pathogenesis in amyotrophic lateral sclerosis\u2014Vulnerability of lower motor neurons to proximal excitotoxicity","volume":"8","author":"Blizzard","year":"2015","journal-title":"Dis. Model. Mech."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fneur.2019.00068","article-title":"Diagnostic challenge and neuromuscular junction contribution to ALS pathogenesis","volume":"10","author":"Campanari","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1007\/s13311-022-01297-6","article-title":"Axon biology in ALS: Mechanisms of axon degeneration and prospects for therapy","volume":"19","author":"Coleman","year":"2022","journal-title":"Neurotherapeutics"},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Eisen, A. (2021). The dying forward hypothesis of ALS: Tracing its history. Brain Sci., 11.","DOI":"10.3390\/brainsci11030300"},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Iyer, A.K., Jones, K.J., Sanders, V.M., and Walker, C.L. (2018). Temporospatial analysis and new players in the immunology of amyotrophic lateral sclerosis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020631"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s40035-022-00331-z","article-title":"TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis","volume":"11","author":"Durcan","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1007\/s12035-021-02658-6","article-title":"Neuromuscular junction dysfunction in amyotrophic lateral sclerosis","volume":"59","author":"Verma","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev.neuro.27.070203.144308","article-title":"Plasticity of the spinal neural circuitry after injury","volume":"27","author":"Edgerton","year":"2004","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.neures.2006.10.001","article-title":"Synaptic plasticity modulates the spontaneous recovery of locomotion after spinal cord hemisection","volume":"57","author":"Gulino","year":"2007","journal-title":"Neurosci. Res."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.brainres.2004.03.055","article-title":"Levels of brain-derived neurotrophic factor and neurotrophin-4 in lumbar motoneurons after low-thoracic spinal cord hemisection","volume":"1013","author":"Gulino","year":"2004","journal-title":"Brain Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/35067570","article-title":"Plasticity of motor systems after incomplete spinal cord injury","volume":"2","author":"Raineteau","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"114178","DOI":"10.1016\/j.expneurol.2022.114178","article-title":"Activity-dependent plasticity and spinal cord stimulation for motor recovery following spinal cord injury","volume":"357","author":"Samejima","year":"2022","journal-title":"Exp. Neurol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1146\/annurev.neuro.24.1.807","article-title":"Activity-dependent spinal cord plasticity in health and disease","volume":"24","author":"Wolpaw","year":"2001","journal-title":"Annu. Rev. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4613\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:43:39Z","timestamp":1760121819000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4613"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,27]]},"references-count":138,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24054613"],"URL":"https:\/\/doi.org\/10.3390\/ijms24054613","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,27]]}}}