Chonnam Med J.  2012 Apr;48(1):1-6. 10.4068/cmj.2012.48.1.1.

Molecular Mechanisms Involved in Depotentiation and Their Relevance to Schizophrenia

• Sanderson

• KMID: 2274874
• DOI: http://doi.org/10.4068/cmj.2012.48.1.1

Abstract

Long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission are forms of synaptic plasticity that have been studied extensively and are thought to contribute to learning and memory. The reversal of LTP, known as depotentiation (DP) has received far less attention however, and its role in behavior is also far from clear. Recently, deficits in depotentiation have been observed in models of schizophrenia, suggesting that a greater understanding of this form of synaptic plasticity may help reveal the physiological alterations that underlie symptoms experienced by patients. This review therefore seeks to summarize the current state of knowledge on DP, and then put the deficits in DP in models of disease into this context.

Keyword

Neuronal plasticity; Long-term potentiation; Long-term synaptic depression; Schizophrenia

MeSH Terms

Depression
Humans
Learning
Long-Term Potentiation
Long-Term Synaptic Depression
Memory
Neuronal Plasticity
Plastics
Schizophrenia
Synaptic Transmission
Plastics

Figure

• 

  FIG. 1 Schematic illustrating the molecular mechanisms involved in DP. DP is caused by LFS or theta pulse stimulation (TP). This causes efflux of cAMP to the extracellular space where it is converted to adenosine. Adenosine then activates Gi/o linked adenosine A1 receptors that act to decrease cAMP levels, possibly abrogating LTP that is dependent on cAMP dependent mechanisms, like PKA. Additionally neuronal activity, NMDA receptors and PP1 cause the trafficking of GIRK channels to the surface, which may then be activated by A1 receptors. NR2A containing NMDA receptors together with Rap2 and JNK also induce AMPA receptor internalization of AMPA receptors containing long C-terminal tails, providing a means by which DP can be expressed. Movements are indicated by yellow arrows, actions are indicated by black arrows.

Reference

1. Barrionuevo G, Schottler F, Lynch G. The effects of repetitive low frequency stimulation on control and "potentiated" synaptic responses in the hippocampus. Life Sci. 1980. 27:2385–2391.

2. Bashir ZI, Collingridge GL. An investigation of depotentiation of long-term potentiation in the CA1 region of the hippocampus. Exp Brain Res. 1994. 100:437–443.

3. Fujii S, Saito K, Miyakawa H, Ito K, Kato H. Reversal of long-term potentiation (depotentiation) induced by tetanus stimulation of the input to CA1 neurons of guinea pig hippocampal slices. Brain Res. 1991. 555:112–122.

4. Staubli U, Lynch G. Stable depression of potentiated synaptic responses in the hippocampus with 1-5 Hz stimulation. Brain Res. 1990. 513:113–118.

5. Huang CC, Liang YC, Hsu KS. A role for extracellular adenosine in time-dependent reversal of long-term potentiation by low-frequency stimulation at hippocampal CA1 synapses. J Neurosci. 1999. 19:9728–9738.

6. Stäubli U, Chun D. Factors regulating the reversibility of long-term potentiation. J Neurosci. 1996. 16:853–860.

7. Staubli U, Chun D. Proactive and retrograde effects on LTP produced by theta pulse stimulation: mechanisms and characteristics of LTP reversal in vitro. Learn Mem. 1996. 3:96–105.

8. Stäubli U, Scafidi J. Time-dependent reversal of long-term potentiation in area CA1 of the freely moving rat induced by theta pulse stimulation. J Neurosci. 1999. 19:8712–8719.

9. Larson J, Xiao P, Lynch G. Reversal of LTP by theta frequency stimulation. Brain Res. 1993. 600:97–102.

10. Buzsáki G. Theta oscillations in the hippocampus. Neuron. 2002. 33:325–340.

11. Huang CC, Liang YC, Hsu KS. Characterization of the mechanism underlying the reversal of long term potentiation by low frequency stimulation at hippocampal CA1 synapses. J Biol Chem. 2001. 276:48108–48117.

12. Zho WM, You JL, Huang CC, Hsu KS. The group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine induces a novel form of depotentiation in the CA1 region of the hippocampus. J Neurosci. 2002. 22:8838–8849.

13. Moult PR, Milojkovic B, Harvey J. Leptin reverses long-term potentiation at hippocampal CA1 synapses. J Neurochem. 2009. 108:685–696.

14. O'Dell TJ, Kandel ER. Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases. Learn Mem. 1994. 1:129–139.

15. Lee HK, Barbarosie M, Kameyama K, Bear MF, Huganir RL. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature. 2000. 405:955–959.

16. Sanderson TM, Cotel MC, O'Neill MJ, Tricklebank MD, Collingridge GL, Sher E. Alterations in hippocampal excitability, synaptic transmission and synaptic plasticity in a neurodevelopmental model of schizophrenia. Neuropharmacology. 2012. 62:1349–1358.

17. Grover LM, Teyler TJ. Two components of long-term potentiation induced by different patterns of afferent activation. Nature. 1990. 347:477–479.

18. Morgan SL, Teyler TJ. VDCCs and NMDARs underlie two forms of LTP in CA1 hippocampus in vivo. J Neurophysiol. 1999. 82:736–740.

19. Fitzjohn SM, Bortolotto ZA, Palmer MJ, Doherty AJ, Ornstein PL, Schoepp DD, et al. The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity. Neuropharmacology. 1998. 37:1445–1458.

20. Kulla A, Manahan-Vaughan D. Modulation by group 1 metabotropic glutamate receptors of depotentiation in the dentate gyrus of freely moving rats. Hippocampus. 2008. 18:48–54.

21. Collingridge GL, Peineau S, Howland JG, Wang YT. Long-term depression in the CNS. Nat Rev Neurosci. 2010. 11:459–473.

22. Liu L, Wong TP, Pozza MF, Lingenhoehl K, Wang Y, Sheng M, et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science. 2004. 304:1021–1024.

23. Massey PV, Johnson BE, Moult PR, Auberson YP, Brown MW, Molnar E, et al. Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J Neurosci. 2004. 24:7821–7828.

24. Zhu Y, Pak D, Qin Y, McCormack SG, Kim MJ, Baumgart JP, et al. Rap2-JNK removes synaptic AMPA receptors during depotentiation. Neuron. 2005. 46:905–916.

25. Arai A, Kessler M, Lynch G. The effects of adenosine on the development of long-term potentiation. Neurosci Lett. 1990. 119:41–44.

26. Fujii S, Sekino Y, Kuroda Y, Sasaki H, Ito K, Kato H. 8-cyclopentyltheophylline, an adenosine A1 receptor antagonist, inhibits the reversal of long-term potentiation in hippocampal CA1 neurons. Eur J Pharmacol. 1997. 331:9–14.

27. Liang YC, Huang CC, Hsu KS. A role of p38 mitogen-activated protein kinase in adenosine A₁ receptor-mediated synaptic depotentiation in area CA1 of the rat hippocampus. Mol Brain. 2008. 1:13.

28. de Mendonça A, Almeida T, Bashir ZI, Ribeiro JA. Endogenous adenosine attenuates long-term depression and depotentiation in the CA1 region of the rat hippocampus. Neuropharmacology. 1997. 36:161–167.

29. Giménez-Llort L, Masino SA, Diao L, Fernández-Teruel A, Tobeña A, Halldner L, et al. Mice lacking the adenosine A1 receptor have normal spatial learning and plasticity in the CA1 region of the hippocampus, but they habituate more slowly. Synapse. 2005. 57:8–16.

30. Brust TB, Cayabyab FS, Zhou N, MacVicar BA. p38 mitogen-activated protein kinase contributes to adenosine A1 receptor-mediated synaptic depression in area CA1 of the rat hippocampus. J Neurosci. 2006. 26:12427–12438.

31. Mulkey RM, Herron CE, Malenka RC. An essential role for protein phosphatases in hippocampal long-term depression. Science. 1993. 261:1051–1055.

32. Lisman J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc Natl Acad Sci U S A. 1989. 86:9574–9578.

33. Nicholls RE, Alarcon JM, Malleret G, Carroll RC, Grody M, Vronskaya S, et al. Transgenic mice lacking NMDAR-dependent LTD exhibit deficits in behavioral flexibility. Neuron. 2008. 58:104–117.

34. Zhuo M, Zhang W, Son H, Mansuy I, Sobel RA, Seidman J, et al. A selective role of calcineurin aalpha in synaptic depotentiation in hippocampus. Proc Natl Acad Sci U S A. 1999. 96:4650–4655.

35. Chung HJ, Ge WP, Qian X, Wiser O, Jan YN, Jan LY. G protein-activated inwardly rectifying potassium channels mediate depotentiation of long-term potentiation. Proc Natl Acad Sci U S A. 2009. 106:635–640.

36. Chung HJ, Qian X, Ehlers M, Jan YN, Jan LY. Neuronal activity regulates phosphorylation-dependent surface delivery of G protein-activated inwardly rectifying potassium channels. Proc Natl Acad Sci U S A. 2009. 106:629–634.

37. Kim JI, Lee HR, Sim SE, Baek J, Yu NK, Choi JH, et al. PI3Kγ is required for NMDA receptor-dependent long-term depression and behavioral flexibility. Nat Neurosci. 2011. 14:1447–1454.

38. Nicolas CS, Peineau S, Amici M, Csaba Z, Fafouri A, Javalet C, et al. The Jak/STAT pathway is involved in synaptic plasticity. Neuron. 2012. 73:374–390.

39. Sanderson TM, Collingridge GL, Fitzjohn SM. Differential trafficking of AMPA receptors following activation of NMDA receptors and mGluRs. Mol Brain. 2011. 4:30.

40. Shi SH, Hayashi Y, Petralia RS, Zaman SH, Wenthold RJ, Svoboda K, et al. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science. 1999. 284:1811–1816.

41. Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R. Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell. 2002. 110:443–455.

42. Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci. 2002. 25:409–432.

43. Owen MJ, Craddock N, O'Donovan MC. Schizophrenia: genes at last? Trends Genet. 2005. 21:518–525.

44. Kwon OB, Longart M, Vullhorst D, Hoffman DA, Buonanno A. Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses. J Neurosci. 2005. 25:9378–9383.

45. Kwon OB, Paredes D, Gonzalez CM, Neddens J, Hernandez L, Vullhorst D, et al. Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors. Proc Natl Acad Sci U S A. 2008. 105:15587–15592.

46. Vullhorst D, Neddens J, Karavanova I, Tricoire L, Petralia RS, McBain CJ, et al. Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. J Neurosci. 2009. 29:12255–12264.

47. Knable MB, Barci BM, Bartko JJ, Webster MJ, Torrey EF. Molecular abnormalities in the major psychiatric illnesses: Classification and Regression Tree (CRT) analysis of post-mortem prefrontal markers. Mol Psychiatry. 2002. 7:392–404.

48. Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci. 2003. 23:6315–6326.

49. Shamir A, Kwon OB, Karavanova I, Vullhorst D, Leiva-Salcedo E, Janssen MJ, et al. The importance of the NRG-1/ErbB4 pathway for synaptic plasticity and behaviors associated with psychiatric disorders. J Neurosci. 2012. 32:2988–2997.

50. McGuffin P, Farmer AE, Gottesman II, Murray RM, Reveley AM. Twin concordance for operationally defined schizophrenia. Confirmation of familiality and heritability. Arch Gen Psychiatry. 1984. 41:541–545.

51. Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, Kamiya A, Brandon NJ, Sawa A. Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci. 2009. 32:485–495.

52. Lodge DJ, Grace AA. Gestational methylazoxymethanol acetate administration: a developmental disruption model of schizophrenia. Behav Brain Res. 2009. 204:306–312.

53. Zhou Q, Poo MM. Reversal and consolidation of activity-induced synaptic modifications. Trends Neurosci. 2004. 27:378–383.