3,5-Dimethyladamantan-1-amine Restores Short-term Synaptic Plasticity by Changing Function of Excitatory Amino Acid Transporters in Mouse Model of Spinocerebellar Ataxia Type 1

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Abstract

Introduction. Memantine is an agent that used for treatment of Alzheimer's type dementia. Memantine considerably reduces the effects of neurodegeneration, may potentially slow down the neurodegenerative changes in the cerebellum and may act as treatment of choice for spinocerebellar ataxia type 1 (SCA 1).

Our objective was to study molecular mechanisms of the short-term synaptic plasticity improvement associated with long-term memantine use in SCA 1 transgenic mice.

Materials and methods. The experiments were performed on 12-week-old CD1 mice. We created a mouse model of cerebellar astrogliosis after expression of mutant ataxin-1 (ATXN1[Q85]) in the Bergmann glia (BG). To model the astrocyte-mediated neurodegeneration in the cerebellum, the mice were injected with LVV GFAP-Flag-ATXN1[Q85] lentiviral vector (LVV) constructs intracortically. Some of the mice received 0.35 mg/kg memantine dissolved in drink water once daily for 9 weeks. The control animals were administered LVV GFAP-ATXN1[Q2]-Flag. Changes of the excitatory postsynaptic currents amplitudes from Purkinje cells (PC) were recorded by patch clamp. Expression of anti-EAAT1 in the cerebellar cortex was assessed using immunohistochemistry.

Results. The reactive glia of the cerebellar cortex in SCA1 mice is characterized by a decrease in the immunoreactivity of anti-EAAT1, while chronic memantine use restores this capacity. The decay time of the excitatory postsynaptic current amplitude in the parallel fiber-Purkinje cell (PF-PC) synapses of the SCA1 mice is considerably longer, which indicates the slowing of glutamate reuptake and EAAT1 dysfunction. The prolonged presence of increased neurotransmitter levels in the synaptic cleft facilitates activation of the mGluR1 signaling and restoration of mGluR1-dependent synaptic plasticity in Purkinje cells of the SCA1 mice.

Conclusions. The slowing of neurotransmitter reuptake associated with long-term memantine treatment improves mGluR1-dependent short-term synaptic plasticity of the Purkinje cells in the SCA1 mice. Restoration of synaptic plasticity in these animals may underlie partial reduction of ataxic syndrome.

About the authors

Olga S. Belozor

Prof. V.F. Voyno-Yasenetsky Krasnoyarsk State Medical University

Email: shuvaevan@krasgmu.ru
ORCID iD: 0000-0001-8384-5962

assistant, Department of biological chemistry with courses of medical, pharmaceutical and toxicological chemistry

Russian Federation, Krasnoyarsk

Alex A. Vasilev

Immanuel Kant Baltic Federal University

Email: shuvaevan@krasgmu.ru
ORCID iD: 0000-0001-9288-842X

researcher, Scientific and educational cluster MEDBIO

Russian Federation, Kaliningrad

Alexandra G. Mileiko

Siberian Federal University

Email: shuvaevan@krasgmu.ru
ORCID iD: 0009-0003-2623-0074

student

Russian Federation, Krasnoyarsk

Liudmila D. Mosina

Siberian Federal University

Email: shuvaevan@krasgmu.ru
ORCID iD: 0009-0001-2839-6161

student

Russian Federation, Krasnoyarsk

Ilya G. Mikhailov

Siberian Federal University

Email: shuvaevan@krasgmu.ru
ORCID iD: 0009-0004-0022-1898

student

Russian Federation, Krasnoyarsk

Andrey N. Shuvaev

Siberian Federal University

Email: shuvaevan@krasgmu.ru
ORCID iD: 0000-0002-3887-1413

Cand. Sci. (Phys.-Math.), Head, Medical and biological systems and complexes department

Russian Federation, Krasnoyarsk

Anton N. Shuvaev

Prof. V.F. Voyno-Yasenetsky Krasnoyarsk State Medical University; Siberian Federal University

Author for correspondence.
Email: shuvaevan@krasgmu.ru
ORCID iD: 0000-0003-0078-4733

Cand. Sci. (Med.), Head, Research Institute of Molecular Medicine and Pathological Biochemistry

Russian Federation, Krasnoyarsk; Krasnoyarsk

References

  1. Opal P., Ashizawa T. Spinocerebellar Ataxia Type 1. In: M.P. Adam (ed.) GeneReviews. Seattle; 1998. doi: 10.1016/j.nbd.2021.105340
  2. Colleen A.S., La Spada A.R. The CAG-polyglutaminerepeat diseases: a clini- cal, molecular, genetic, and pathophysiologic nosology. Handbook of Clinical Neurology. 2018;147:143–170. doi: 10.1016/B978-0-444-63233-3.00011-7
  3. Paulson H.L., Shakkottai V.G., Clark H.B., Orr H.T. Polyglutamine spinocerebellar ataxias — from genes to potential treatments. Nat. Rev. Neurosci. 2017;18(10):613–626. doi: 10.1038/nrn.2017.92
  4. Lam Y.C., Bowman A.B., Jafar-Nejad P. et al. ATAXIN-1 interacts with the repressor capicua in its native complex to cause SCA1 neuropathology. Cell. 2006;127(7):1335–1347. doi: 10.1016/j.cell.2006.11.038
  5. Burright E.N., Clark H.B., Servadio A. et al. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell. 1995;82(6):937–948. doi: 10.1016/0092-8674(95)90273-2
  6. Shuvaev A.N., Belozor O.S., Mozhei O., et al. Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1.Neurobiol.Disease. 2021;154:105340. doi: 10.1016/j.nbd.2021.105340
  7. Shuvaev A.N., Hosoi N., Sato Y., el al. Progressive impairment of cerebellar mGluR signalling and its therapeutic potential for cerebellar ataxia in spino- cerebellar ataxia type 1 model mice. J. Physiol. 2017;595(1):141–164. doi: 10.1113/JP272950
  8. Matilla A., Roberson E.D., Banfi S. et al. Mice lacking ataxin-1 display learning deficits and decreased hippocampal paired-pulse facilitation. J. Neurosci. 1998;18(14):5508–5516. doi: 10.1523/JNEUROSCI.18-14-05508.1998
  9. Schmitt A., Asan E., Püschel B, Kugler P. Cellular and regional distribution of the GLAST glutamate transporter in the rat CNS: non-radioactive in situ hybridization and comparative immunocytochemistry. J. Neurosci.1997;17:1–10. doi: 10.1523/JNEUROSCI.17-01-00001.1997
  10. Todd A.C., Hardingham G.E. The regulation of astrocytic glutamate transporters in health and neurodegenerative diseases. Int. J. Mol. Sci. 2020; 21(24):9607. doi: 10.3390/ijms21249607
  11. Choi D.W. Excitotoxic cell death. J. Neurobiol. 1992;23(9):1261–1276. doi: 10.1002/neu.480230915
  12. Hardingham G.E., Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: Implications for neurodegenerative disorders. Nat. Rev. Neurosci. 2010;11:682–696. doi: 10.1038/nrn2911
  13. Heidrich A., Rösler M., Riederer P. Pharmakotherapiebei Alzheimer-Demenz: Therapiekognitiver Symptomeneue Studienresultate Fortschr. Neurol. Psychiatr. 1997;65(3):108–121. doi: 10.1055/s-2007-996315
  14. Aljuwaiser M., Alayadhi N., Ozidu V. et al. Clinical indications of memantine in psychiatry-science or art? Psychopharmacol. Bull. 2023;53(1):30–38.
  15. Cummings C.J., Reinstein E., Sun Y. et al. Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron. 1999;24(4):879–892. doi: 10.1016/s0896-6273(00)81035-1
  16. Pichardo-Rojas D., Pichardo-Rojas P.S., Cornejo-Bravo J.M., Serrano-Medina A. Memantine as a neuroprotective agent in ischemic stroke: preclinical and clinical analysis. Front. Neurosci. 2023;17:1096372. doi: 10.3389/fnins.2023.1096372
  17. Podkowa K., Czarnacki K., Borończyk A. et al. The NMDA receptor anta- gonists memantine and ketamine as anti-migraine agents. Naunyn Schmiedebergs Arch. Pharmacol. 2023;396(7):1371–1398. doi: 10.1007/s00210-023-02444-2
  18. Alzarea S., Abbas M., Ronan P.J. et al. The effect of an α-7 nicotinic allosteric modulator PNU120596 and NMDA receptor antagonist memantine on depressive-like behavior induced by LPS in mice: the involvement of brain microglia. Brain Sci. 2022;12(11):1493. doi: 10.3390/brainsci12111493
  19. Шуваев А.Н., Белозор О.С., Можей О.И. и др. Влияние реактивной глии Бергмана на кратковременную синаптическую пластичность в моделях мозжечковой нейродегенерации, вызванной хронической активацией ChR2 и экспрессией мутантного атаксина 1. Анналы клинической и экспериментальной неврологии. 2021;15(1):51–58. Shuvaev А.N., Belozor О.S., Mozjei O.I. et al. The effect of reactive Bergmann glia on short-term synaptic plasticity in cerebellar neurodegenerative models, caused by chronic activation of ChR2 and expression of the mutant ataxin-1. Annals of clinical and experimental neurology.2021;15(1):51–58.doi: 10.25692/ACEN.2021.1.6
  20. Liu B., Paton J.F., Kasparov S. Viral vectors based on bidirectional cell-specific mammalian promoters and transcriptional amplification strategy for use in vitro and in vivo. BMC Biotechnol. 2008;8:49. doi: 10.1186/1472-6750-8-49
  21. Hewinson J., Paton J.F., Kasparov S. Viral gene delivery: optimized protocol for production of high titer lentiviral vectors. Methods Mol. Biol. 2013;998:65–75. doi: 10.1007/978-1-62703-351-0_5
  22. Bachmanov A.A., Reed D.R., Beauchamp G.K., Tordoff M.G. Food intake, water intake, and drinking spout side preference of 28 mouse strains. Behav. Genet. 2002;32(6):435–443. doi: 10.1023/A:1020884312053
  23. Shuvaev A.N., Belozor O.S., Mozheiet O.I. et al. Indirect negative effect of mutant ataxin-1 on short- and long-term synaptic plasticity in mouse models of spinocerebellar ataxia type 1. Cells. 2022;11(14):2247. doi: 10.3390/cells11142247
  24. Maejima T., Hashimoto K., Yoshida T. et al. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron. 2001;31:463–475. doi: 10.1016/s0896-6273(01)00375-0
  25. Brown S.P., Brenowitz S.D., Regehr W.G. Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids. Nat. Neurosci. 2003;6:1048–1057. doi: 10.1038/nn1126
  26. Marcaggi P., Attwell D. Endocannabinoid signaling depends on the spatial pattern of synapse activation. Nat. Neurosci. 2005;8(6):776–781. doi: 10.1038/nn1458
  27. Marcaggi P., Attwell D. Short- and long-term depression of rat cerebellar parallel fibre synaptic transmission mediated by synaptic crosstalk. J. Physiol. 2007;578:545–550. doi: 10.1113/jphysiol.2006.115014
  28. Parkin G.M., Udawela M., Gibbons A., Dean B. Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders. World J. Psychiatry. 2018;8(2):51–63. doi: 10.5498/wjp.v8.i2.51.
  29. Duan S., Anderson C.M., Stein B.A., Swanson R.A. Glutamate induces ra- pid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. J. Neurosci. 1999;19:10193–10200. doi: 10.1523/JNEUROSCI.19-23-10193.1999
  30. Zimmer E.R., Torrez V.R., Kalinine E. et al. Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with anxiety-like phenotype. Front. Cell. Neurosci. 2015;3:219. doi: 10.3389/fncel.2015.00219
  31. Serra H.G., Byam C.E., Lande J.D. et al. Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum. Mol. Genet. 2004;13(20):2535–2543. doi: 10.1093/hmg/ddh268
  32. Notartomaso S., Zapulla C., Biagioni F. et al. Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1. Mol. Brain. 2013;6:48. doi: 10.1186/1756-6606-6-48
  33. Power E.M., Morales A., Empson R.M. Prolonged type 1 metabotropic glutamate receptor dependent synaptic signaling contributes to spino-cerebellar ataxia type 1. J. Neurosci. 2016;36(1):4910–4916. doi: 10.1523/jneurosci.3953-15.2016
  34. Cvetanovic M. Decreased expression of glutamate transporter GLAST in Bergmann glia is associated with the loss of Purkinje neurons in the spino- cerebellar ataxia type 1. Cerebellum. 2014;14(1):8–11. doi: 10.1007/s12311-014-0605-0
  35. Tabata T., Kano M. In: Handbook of Neurochemistry and Molecular Neurobiology. N.Y.; 2009:63–86.
  36. Jin Y., Kim S.J., Kim J. et al. Long-term depression of mGluR1 signaling. Neuron. 2007;55(2):277–287. doi: 10.1016/j.neuron.2007.06.035

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2. Fig. 1. EAAT1 expression in animals receiving and not receiving memantine. A — fluorescent microphotographs of the cerebellar cortex slices labeled with anti-EAAT1 (left panel). The images processed with ImageJ software (right panel). Chart scales are 50 and 5 μm respectively. B — proportion of anti-EAAT1 positive signal area. C — total amount of anti-EAAT1 positive spots. а/n — number of examined areas/animals. **p < 0.01.

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3. Fig. 2. Memantine increases the constant decay time (τ) of PF-EPSC amplitude in the PC of SCA1 mice. Summary diagram of the PF-EPSCs mean constant decay time (τ). Representative curves are presented on the right panel. c/n is the number of cells/animals (*p < 0.05).

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4. Fig. 3. The SSE impairment after the inhibition of mGluR1-dependent signaling pathway in the presence of СРССОЕt. A — changes of PF-EPSC amplitudes after tetanic PF stimulation. Representative PF-EPSC curves above the chart: recorded immediately before the stimulation (point 1, 10 sec on the time axis) and after the stimulation (point 2, 0 sec on the time axis). B — amplitudes normalized to the pre-stimulation level immediately after the stimulation (point 2). с/n is the number of cells/animals. *p < 0.05.

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5. Fig. 4. SSE restoration in SCA1 mice after long-term memantine administration (mem). A — changes of PF-EPSC amplitudes after tetanic PF stimulation. Representative PF-EPSC curves above the chart: recorded immediately before the stimulation (point 1, 10 s on the time axis) and after the stimulation (point 2, 0 s on the time axis). B — amplitudes normalized to the pre-stimulation level immediately after the stimulation (point 2). с/n is the number of cells/animals. **p < 0.01; ***p < 0.001.

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Copyright (c) 2024 Belozor O.S., Vasilev A.A., Mileiko A.G., Mosina L.D., Mikhailov I.G., Shuvaev A.N., Shuvaev A.N.

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