Susceptibility to Aβo and TBOA of LTD and Extrasynaptic NMDAR-Dependent Tonic Current in the Aged Rat Hippocampus
Aging, as the major risk factor of Alzheimer’s disease (AD), may increase susceptibility to neurodegenerative diseases through many gradual molecular and biochemical changes. Extracellular glutamate homeostasis and extrasynaptic glutamate N-methyl-D-aspartate receptors (NMDAR) are among early synaptic targets of oligomeric amyloid β (Aβo), one of the AD related synaptotoxic protein species. In this study, we asked for the effects of Aβo on long-term depression (LTD), a form of synaptic plasticity dependent on extrasynaptic NMDAR activation, and on a tonic current (TC) resulting from the activation of extrasynaptic NMDAR by ambient glutamate in hippocampal slices from young (3–6-month-old) and aged (24–28-month-old) Sprague–Dawley rats. Aβo significantly enhanced the magnitude of LTD and the amplitude of TC in aged slices compared to young ones. TBOA, a glutamate transporter inhibitor, also significantly increased LTD magnitude and TC amplitude in slices from aged rats, suggesting either an age-related weakness of the glutamate clearance system and/or a facilitated extrasynaptic NMDAR activation. From our present data, we hypothesize that senescence-related impairment of the extrasynaptic environment may be a vector of vulnerability of the aged hippocampus to neurodegenerative promotors such as Aβo.
KeywordsAging Tonic current Extracellular glutamate Synaptic plasticity NMDA receptors Alzheimer
This work was supported in part by INSERM. The authors are grateful to the animal caretakers of the CPN.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 21.Potier B, Billard JM, Riviere S, Sinet PM, Denis I, Champeil-Potokar G, Grintal B, Jouvenceau A, Kollen M, Dutar P (2010) Reduction in glutamate uptake is associated with extrasynaptic NMDA and metabotropic glutamate receptor activation at the hippocampal CA1 synapse of aged rats. Aging Cell 9:722–735CrossRefPubMedGoogle Scholar
- 27.Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L (2000) High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058CrossRefPubMedGoogle Scholar
- 28.Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Huang S, Tong H, Lei M, Zhou M, Guo W, Li G, Tang X, Li Z, Mo M, Zhang X, Chen X, Cen L, Wei L, Xiao Y, Li K, Huang Q, Yang X, Liu W, Zhang L, Qu S, Li S, Xu P (2018) Astrocytic glutamatergic transporters are involved in Aβ-induced synaptic dysfunction. Brain Res 1678:129–137CrossRefPubMedGoogle Scholar
- 32.Kervern M, Angeli A, Nicole O, Leveille F, Parent B, Villette V, Buisson A, Dutar P (2012) Selective impairment of some forms of synaptic plasticity by oligomeric amyloid-beta peptide in the mouse hippocampus: implication of extrasynaptic NMDA receptors. J Alzheimers Dis 32:183–196CrossRefPubMedGoogle Scholar
- 35.Audrain M, Fol R, Dutar P, Potier B, Billard JM, Flament J, Alves S, Burlot MA, Dufayet-Chaffaud G, Bemelmans AP, Valette J, Hantraye P, Deglon N, Cartier N, Braudeau J (2016) Alzheimer’s disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression. Mol Neurodegener 11:016–0070CrossRefGoogle Scholar
- 42.Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, Dziewczapolski G, Nakamura T, Cao G, Pratt AE, Kang YJ, Tu S, Molokanova E, McKercher SR, Hires SA, Sason H, Stouffer DG, Buczynski MW, Solomon JP, Michael S, Powers ET, Kelly JW, Roberts A, Tong G, Fang-Newmeyer T, Parker J, Holland EA, Zhang D, Nakanishi N, Chen HS, Wolosker H, Wang Y, Parsons LH, Ambasudhan R, Masliah E, Heinemann SF, Pina-Crespo JC, Lipton SA (2013) Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A 110:17CrossRefGoogle Scholar