Depotentiation of Long-Term Potentiation Is Associated with Epitope-Specific Tau Hyper-/Hypophosphorylation in the Hippocampus of Adult Rats
- 82 Downloads
It is well-known that some kinases which are involved in the induction of synaptic plasticity probably modulate tau phosphorylation. However, how depression of potentiated synaptic strength contributes to tau phosphorylation is unclear because of the lack of experiments in which depotentiation of LTP was induced. Field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded from the dentate gyrus in response to the perforant pathway stimulation. To induce LTP, high-frequency stimulation (HFS) was used, while, for depotentiation of LTP, low-frequency stimulation (LFS) consisting of 900 pulses at 1 Hz was applied 5 min after tetanization. In some experiments, a neutral protocol at 0.033 Hz was applied throughout the experiment without any induction of synaptic plasticity. One-hertz depotentiation protocol was able to decrease fEPSP slope which was previously increased by HFS, whereas no significant change in fEPSP slope and PS amplitude was observed in neutral protocol experiments. Relative to saline infusion, LTP was lower in magnitude and was more reversed by subsequent LFS in the presence of ERK1/2 inhibitor. Western blot experiments indicated that tau protein was hyperphosphorylated at ser416 epitope but rather hypophosphorylated at thr231 epitope in the whole hippocampus upon depotentiation of LTP. These changes concomitantly occurred with a notable increase in the levels of total tau and in the levels of phosphorylated form of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). ERK1/2 inhibition resulted in a decrease in phosphorylation of tau at p416Tau when ERK1/2 was inhibited. These findings indicate that some forms of long-term plastic changes might be related with epitope-specific tau phosphorylation and ERK1/2 activation in the hippocampus. Therefore, we emphasize that tau may be crucial for physiological learning as well as Alzheimer’s disease pathology.
KeywordsDepotentiation Alzheimer’s disease pathology Extracellular signal-regulated protein kinases 1/2 Tau proteins Hippocampus
Support was from the Scientific and Technological Research Council of Turkey (TUBITAK) for providing the Student Laboratory Experience Grant. This research was financially supported by Erciyes University Research Found grant number TDK-2016-6628 to C.S.
Compliance with ethical standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
- Akirav I, Richter-Levin G (1999) Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat.. J Neurosci 19:10530–10535Google Scholar
- Artis AS, Bitiktas S, Taşkın E, Dolu N, Liman N, Suer C (2012) Experimental hypothyroidism delays field excitatory post-synaptic potentials and disrupts hippocampal long-term potentiation in the dentate gyrus of hippocampal formation and Y-maze performance in adult rats. J Neuroendocrinol 24(3):422–433CrossRefGoogle Scholar
- Gomez-Ramos A et al (2004) Tau phosphorylation and assembly. Acta Neurobiol Exp (Wars) 64(1):33–39Google Scholar
- Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, Brown C, Hashikawa T, Murayama M, Seok H, Sotiropoulos I, Kim E, Collingridge GL, Takashima A, Cho K (2014) Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Philos Trans R Soc B 369:20130144CrossRefGoogle Scholar
- O’reilly RC, Norman KA, McClelland JL (1998) A hippocampal model of recognition memory. In: Advances in neural information processing systems, pp 73–79Google Scholar
- Pei JJ, Gong CX, An WL, Winblad B, Cowburn RF, Grundke-Iqbal I, Iqbal K (2003) Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK-1/2, and p70 S6, similar to that in Alzheimer’s disease. Am J Pathol 163(3):845–858CrossRefGoogle Scholar
- Racaniello M, Cardinale A, Mollinari C, D’Antuono M, de Chiara G, Tancredi V, Merlo D (2010) Phosphorylation changes of CaMKII, ERK1/2, PKB/Akt kinases and CREB activation during early long-term potentiation at Schaffer collateral-CA1 mouse hippocampal synapses. Neurochem Res 35(2):239–246CrossRefGoogle Scholar
- Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L (2011) Amyloid-beta/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci 31(2):700–711CrossRefGoogle Scholar
- Steiner B, Mandelkow EM, Biernat J, Gustke N, Meyer HE, Schmidt B, Mieskes G, Söling HD, Drechsel D, Kirschner MW, Goedert M, Mandelkow E (1990) Phosphorylation of microtubule-associated protein tau: identification of the site for Ca2(+)-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. EMBO J 9(11):3539–3544CrossRefGoogle Scholar
- Yang Q, Zhu G, Liu D, Ju J-G, Liao Z-H, Xiao Y-X, Zhang Y, Chao N, Wang J, Li W (2017) Extrasynaptic NMDA receptor dependent long-term potentiation of hippocampal CA1 pyramidal neurons. Sci Rep 7:3045. https://www.nature.com/articles/s41598-017-03287-7. Accessed 22 Sept 2018