Abstract
Spinal cord injury (SCI) causes motor impairment and the proper excitation/inhibition balance in motoneurons is important for recovery. Diabetes mellitus impairs regenerative capacity following SCI. The purpose of this study was to assess the short-term plasticity (STP) of lumbar spinal cord motoneurons in conditions of (1) lateral hemisection (SCI), (2) fructose-induced diabetes (D), and (3) diabetes associated with hemisection (D + SCI). We show that in the cases of SCI, D, and D + SCI, the ratio of percentage share of excitatory and inhibitory combinations of motoneurons responses to high-frequence stimulation of sciatic nerve is multidirectional. In the SCI and D + SCI groups, the cumulative changes in generalized baseline frequencies decreased significantly. When we compared the cumulative changes in the intensity of excitatory and inhibitory responses relative to baseline during high-frequency stimulation (tetanization epoch), we found that there was a significant intensification in tetanic depression in the D + SCI groups versus SCI, as well as an intensification in tetanic potentiation in the D + SCI vs. D and D + SCI vs. SCI groups. Thus, in conditions of traumatic and/or metabolic pathology, the distinct synaptic inputs exhibit opposing plasticity for homeostatic control of neurotransmission and these integral changes most likely shape postsynaptic STP in the spinal motor network.
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References
Alessandri B, Bullock R (1998) Glutamate and its receptors in the pathophysiology of brain and spinal cord injuries. Prog Brain Res 116:303–330
Anderson NJ, King MR, Delbruck L, Jolivalt CG (2014) Role of insulin signaling impairment, adiponectin and dyslipidemia in peripheral and central neuropathy in mice. Dis Model Mech 7:625–633
Bareyre FM, Kerschensteiner M, Raineteau O, Mettenleiter TC, Weinmann O, Schwab ME (2004) The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci 7:269–277
Bartley AF, Dobrunz LE (2015) Short-term plasticity regulates the excitation/inhibition ratio and the temporal window for spike integration in CA1 pyramidal cells. Eur J Neurosci 41:1402–1415
Benitez SU Carneiro EM Rodrigues de Oliveira AL (2015) Synaptic input changes to spinal cord motoneurons correlate with motor control impairments in a type 1 diabetes mellitus model. Brain and Behavior. 5:e00372
Ang BRG, Yu GF (2018) The role of fructose in type 2 diabetes and other metabolic diseases. J Nutr Food Sci. 8:1
Bertuzzi M, Chang W, Ampatzis K (2018) Adult spinal motoneurons change their neurotransmitter phenotype to control locomotion. Proc Natl Acad Sci USA 115:E9926–E9933
Blakely SR, Hallfrisch J, Reiser S, Prather ES (1981) Long-term effects of moderate fructose feeding on glucose tolerance parameters in rats. J Nutr 111:307–314
Boulenguez P, Liabeuf S, Bos R et al (2010) Down-regulation of the potassiumchloride cotransporter KCC2 contributes to spasticity after spinal cord injury. Nat Med 16:302–307
Bray GA, Nielsen SJ, Popkin BM (2004) Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 79:537–543
Chavushyan V, Soghomonyan A, Karapetyan G, Simonyan K, Yenkoyan K (2020) Disruption of cholinergic circuits as an area for targeted drug treatment of Alzheimer’s disease: in vivo assessment of short-term plasticity in rat brain. Pharmaceuticals 13(297):1–12
Chavushyan VA, Simonyan KV, Simonyan RM, Isoyan AS, Simonyan GM, Babakhanyan MA, Hovhannisyian LE, Nahapetyan KhH, Avetisyan LG, Simonyan MA (2017) Effects of stevia on synaptic plasticity and NADPH oxidase level of CNS in conditions of metabolic disorders caused by fructose. BMC Complement Altern Med 17:540
Chen BK, Knight AM, Madigan NN, Gross L, Dadsetan M, Nesbitt JJ, Rooney GE, Currier BL, Yaszemski MJ, Spinner RJ et al (2011) Comparison of polymer scaffolds in rat spinal cord: a step toward quantitative assessment of combinatorial approaches to spinal cord repair. Biomaterials 32:8077–8086
Cheng RD, Ren W, Sun P, Tian L, Zhang L, Zhang J, Ye XM (2020) Spinal cord injury causes insulin resistance associated with PI3K signaling pathway in hypothalamus. Neurochem Int. 140:104839
Christie JM, Jahr CE (2006) Multivesicular release at Schaffer collateral-CA1 hippocampal synapses. J Neurosci 26:210–216
Christopher W, MacDonell JW et al (2017) α-Motoneurons maintain biophysical heterogeneity in obesity and diabetes in Zucker rats. J Neurophysiol 118:2318–2327
Dietz V, Fouad K (2014) Restoration of sensorimotor functions after spinal cord injury. Brain 137:654–667
Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ (2002) Fructose, weight gain, and the insulin resistance syndrome. Am J Clin Nutr 76:911–922
Filipp ME, Travis BJ, Henry SS, Idzikowski EC, Magnuson SA, Loh MY, Hellenbrand DJ, Hanna AS (2019) Differences in neuroplasticity after spinal cord injury in varying animal models and humans. Neural Regen Res 14:7–19
Filli L, Schwab ME (2015) Structural and functional reorganization of propriospinal connections promotes functional recovery after spinal cord injury. Neural Regen Res 10:509–513
Foster KA, Crowley JJ, Regehr WG (2005) The influence of multivesicular release and postsynaptic receptor saturation on transmission at granule cell to Purkinje cell synapses. J Neurosci 25:11655–11665
Gamper N, Lezanne O (2015) Redox and nitric oxide-mediated regulation of sensory neuron ion channel function. Antioxid Redox Signal 22:486–504
Gerasimenko Y, Gorodnichev R, Moshonkina T, Sayenko D et al (2015) Transcutaneous electrical spinal-cord stimulation in humans. Ann Phys Rehabil Med 58:225–231
Gerasimenko Y, Roy RR, Edgerton VR (2008) Epidural stimulation: comparison of the spinal circuits that generate and control locomotion in rats, cats and humans. Exp Neurol 209:417–425
Giachello CN, Baines RA (2017) Regulation of motoneuron excitability and the setting of homeostatic limits. Curr Opin Neurobiol 43:1–6
Goel P, Nishimura S, Chetlapalli K, Li X, Chen C, Dickman D (2020) Distinct target-specific mechanisms homeostatically stabilize transmission at pre- and post-synaptic compartments. Front Cell Neurosci 14:196
Gogeascoechea A et al (2020) Interfacing with alpha motor neurons in spinal cord injury patients receiving trans-spinal electrical stimulation. Front Neurol
Goldshmit Y, Lythgo N, Galea MP, Turnley AM (2008) Treadmill training after spinal cord hemisection in mice promotes axonal sprouting and synapse formation and improves motor recovery. J Neurotrauma 25:449–465
Gorgey AS, Dolbow DR, Dolbow JD, Khalil RK et al (2014) Effects of spinal cord injury on body composition and metabolic profile – Part I. J Spinal Cord Med 37:693–702
Gwak YS, Tan HY, Nam TS, Paik KS, Hulsebosch CE, Leem JW (2006) Activation of spinal GABA receptors attenuates chronic central neuropathic pain after spinal cord injury. J Neurotrauma 23:1111–1124
Halliwell B, Gutteridge J (2008) Free radicals in biology and medicine, 3rd ed. Oxford University Press
Herrmann A, Gerstner W (2002) Noise and the PSTH response to current transients: II. Integrate-and-fire model with slow recovery and application to motoneuron data. J Comput Neurosci. 12:83–95
Hong S, Ratté S et al (2012) Single neuron firing properties impact correlation-based population coding. J Neurosci 32:1413–1428
Ichiyama RM, Gerasimenko YP, Zhong H, Roy RR, Edgerton VR (2005) Hindlimb stepping movements in complete spinal rats induced by epidural spinal cord stimulation. Neurosci Lett 383:339–344
Iyer P, Beck EJ, Walton KL (2021) A systematic review of the effect of dietary interventions on cardiovascular disease risk in adults with spinal cord injury. J Spinal Cord Med 44:184–203
Jacob TC, Bogdanov YD, Magnus C, Saliba RS, Kittler JT, Haydon PG, Moss SJ (2005) Gephyrin regulates the cell surface dynamics of synaptic GABAA receptors. J Neurosci 25:10469–10478
Kamsler A, Segal M (2004) Hydrogen peroxide as a diffusible signal molecule in synaptic plasticity. Mol Neurobiol 29:167–178
Klyachko VA, Stevens CF (2006) Excitatory and feed-forward inhibitory hippocampal synapses work synergistically as an adaptive filter of natural spike trains. PLoS Biol. 4:e207
Lee-Kubli C, Mixcoatl-Zecuatl T, Jolivalt CG, Calcutt NA (2014) Animal models of diabetes-induced neuropathic pain. In Current Topics in Behavioral Neurosciences 20:147–170
Leem JW et al (2010) Ionotropic glutamate receptors contribute to maintained neuronal hyperexcitability following spinal cord injury in rats. Exp Neurol 224:321–324
Lozano I, Van der Werf R, Bietiger W, Seyfritz E, Peronet C et al (2016) High-fructose and high-fat diet-induced disorders in rats: impact on diabetes risk, hepatic and vascular complications. Nutr Metab 13:1–13
Maffei A, Fontanini A (2009) Network homeostasis: a matter of coordination. Curr Opin Neurobiol 19:168–7360
Magnuson DS, Lovett R, Coffee R, Gray R, Han YZ et al (2005) Functional consequences of lumbar spinal cord contusion injuries in the adult rat. J Neurotrauma 22:529–543
Moreno A, Morris RG, Canals S (2016) Frequency-dependent gating of hippocampal-neocortical interactions. Cereb Cortex 26:2105–2114
Muramatsu K (2020) Diabetes mellitus-related dysfunction of the motor system. Int J Mol Sci 21:7485
Murray KC, Nakae A, Stephens MJ et al (2010) Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nat Med 16:694–700
Nicolopoulos-Stournaras S, Iles JF (1983) Motor neuron columns in the lumbar spinal cord of the rat. J Comp Neurol 217:75–85
Nolan CJ, Damm P, Prentki M (2011) Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet 378:169–181
Nyby MD, Abedi K, Smutko V, Eslami P, Tuck ML (2007) Vascular angiotensin type 1 receptor expression is associated with vascular dysfunction, oxidative stress and inflammation in fructose-fed rats. Hypertens Res 30:451–457
Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates: Compact, 6th edn. Academic Press, Cambridge, MA, USA
Pellegrini-Giampietro DE, Cherici G, Alesiani M et al (1990) Excitatory amino acid release and free radical formation may cooperate in the genesis of ischemia-induced neuronal damage. J Neurosci 10:1035–1041
Raineteau O, Schwab ME (2001) Plasticity of motor systems after incomplete spinal cord injury. Nat Rev Neurosci 2:263–273
Ramírez-Jarquín UN, Tapia R (2018) Excitatory and inhibitory neuronal circuits in the spinal cord and their role in the control of motor neuron function and degeneration. ACS Chem Neurosci. 9, 211–216
Ramji N, Toth C, Kennedy J, Zochodne DW (2007) Does diabetes mellitus target motor neurons? Neurobiol Dis 26:301–311
Regehr WG (2012) Short-term presynaptic plasticity. Cold Spring Harb Perspect Biol. 4:a005702
Rioult-Pedotti MS, Donoghue JP, Dunaevsky A (2007) Plasticity of the synaptic modification range. J Neurophysiol 98:3688–3695
Rosenzweig ES, McDonald JW (2004) Rodent models for treatment of spinal cord injury: research trends and progress toward useful repair. Curr Opin Neurol 17:121–131
Sadlaoud K, Tazerart S, Brocard C, Jean-Xavier C, Portalier P, Brocard F, Vinay L, Bras H (2010) Differential plasticity of the GABAergic and glycinergic synaptic transmission to rat lumbar motoneurons after spinal cord injury. J Neurosci 30:3358–3369
Schmidt BJ (2018) Locomotor recovery after lumbar spinal cord injury: fact or fancy? J Physiol 596:137–138
Scott P, Cowan AI, Stricker C (2012) Quantifying impacts of short-term plasticity on neuronal information transfer. Phys Review E statistical, nonlinear, and soft matter Phys. 85:041921
Simonyan KV, Avetisyan LG, Chavushyan VA (2016) Goji fruit (Lycium barbarum) protects sciatic nerve function against crush injury in a model of diabetic stress. Pathophysiology 23:169–179
Simonyan KV, Chavushyan VA, Lorikyan AG, Simonyan RM, Avetisyan LG, Isoyan AS, Simonyan GM, Simonyan MA (2020) NADPH oxidase and superoxide-producing associates in cells of the spinal cord and bone marrow in diabetic rats with spinal cord injury. Neurophysiology 52:423–429
Sussillo D, Toyoizumi T, Maass W (2007) Self-tuning of neural circuits through short-term synaptic plasticity. J Neurophysiol 97:4079–4095
Spinal Research News (2015) release http://www.spinal-research.org/14657-2/. Accessed 28 April 2016
Talac R, Friedman JA, Moore MJ, Lu L, Jabbari E, Windebank AJ, Currier BL, Yaszemski MJ (2004) Animal models of spinal cord injury for evaluation of tissue engineering treatment strategies. Biomaterials 25:1505–1510
Tappy L, Le KA (2010) Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev 90:23–46
Tejada-Simon MV, Serrano F, Villasana LE, Kanterewicz BI, Wu GY, Quinn MT, Klann E (2005) Synaptic localization of a functional NADPH oxidase in the mouse hippocampus. Mol Cell Neurosci 29:97–106
Toop CR, Gentili Sh (2016) Fructose beverage consumption induces a metabolic syndrome phenotype in the rat: a systematic review and meta-analysis. Nutrients 8:577
Wadiche JI, Jahr CE (2001) Multivesicular release at climbing fiber-Purkinje cell synapses. Neuron 32:301–313
Wang H, Sun RQ, Zeng XY, Zhou X, Li S, Jo E et al (2015) Restoration of autophagy alleviates hepatic ER stress and impaired insulin signalling transduction in high fructose-fed male mice. Endocrinology 156:169–181
Ward JD, Baker RWR, Davis BH (1972) Effect of blood sugar control on the accumulation of sorbitol and fructose in nervous tissues. Diabetes 21:1173–1178
William A et al (2001) Invited review carbohydrate and lipid metabolism in chronic spinal cord injury. J Spinal Cord Med 24:266–277
Xu GY, Hughes MG, Ye Z et al (2004) Concentrations of glutamate released following spinal cord injury kill oligodendrocytes in the spinal cord. Exp Neurol 187:329–336
Zochodne DW, Ramji N, Toth C (2008) Neuronal targeting in diabetes mellitus: a story of sensory neurons and motor neurons. Neuroscientist 14:311–318
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This work was supported by the State Committee of Science RA (Research project 19YR-1F010).
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Study concept and design: K.S., L.A., and V.C. Acquisition of data: K.S., L.A., and V.C. Analysis and interpretation of the data: K.S., V.C., L.A, and A.I. Drafting of the manuscript: K.S., L.A., and V.C.
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The experimental protocol corresponded to the conditions of the European Communities Council Directive (2010/63/UE) and it was approved by the Ethics committee of the Yerevan State Medical University after Mkhitar Heratsi (Approval code-N4 IRB, November 15, 2018).
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Simonyan, K., Avetisyan, L., Isoyan, A. et al. Plasticity in Motoneurons Following Spinal Cord Injury in Fructose-induced Diabetic Rats. J Mol Neurosci 72, 888–899 (2022). https://doi.org/10.1007/s12031-021-01958-9
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DOI: https://doi.org/10.1007/s12031-021-01958-9