暴露治療法(exposure therapy)是指讓病人暴露在各種不同的刺激性情境之中，使之逐漸耐受並能適應的一類認知行為治療的方法。它是治療創傷後壓力症候群、社交恐懼症和強迫症等精神性症狀最常用的行為療法，絕大多數焦慮性疾病的治療可以採用暴露療法，透過與情緒反應有關的誘發刺激，通過有步驟地重複暴露取得適應並消除病人的情緒反應。

釵h證據指出，記憶的消除模式（extinction training）並不會將原本的記憶擦除殆盡，而是形成一種新的抑制性的學習過程，進而防止原本已經存在的記憶表現。但這種透過NMDA受體活化調控所促進的恐懼記憶消除究竟是一種全新的抑制性記憶增強，還是舊有恐懼記憶的部分消除，仍然是需要進一步探討的。於是我們的研究透過恐懼制約與記憶消除的動物模式探討增強NMDA受體glycine modulatory site突觸反應的NMDA受體部分致效劑D-cycloserine(DCS)與glycine transporter(GlyT)抑制劑NFPS對於恐懼記憶消除過程的影響。

此論文的研究共分為三部分。其中在第一部份的研究中，我們先探討作用於NMDA受體glycine modulatory site的部分致效劑DCS對於恐懼記憶消除分子機制層面的影響。發現在恐懼制約訓練後1小時，當恐懼記憶尚未完全固化時給予記憶消除訓練模式，可以逆轉原本伴隨恐懼記憶形成的突觸與細胞膜表面AMPA受體GluR1次體增加情形與恐懼反應。然而，記憶消除訓練若在制約後24小時當恐懼記憶已完全固化時才給予，增加的恐懼反應會被降低，但增加的突觸與細胞膜表面GluR1次體卻未受影響。於是我們將NMDA受體部份致效劑DCS於記憶消除訓練執行前30分鐘投入大腦兩側的杏仁核區，發現不但可更進一步增強記憶消除訓練造成的恐懼反應降低程度，同時也降低了原本被恐懼制約增加的細胞膜表面GluR1次體。將刺激電極置於杏仁核腦切片的external capsule (EC)部位誘導高頻電刺激，可增加杏仁核側核神經元(LA neurons)的突觸反應且持續超過2個小時，若在刺激後1小時當長期增益現象已完全固化時給予低頻電刺激，並不會對已增加的突觸反應產生影響，然而若在執行低頻電刺激的同時給予DCS則可成本冗犮h增益現象(depotentiation)與逆轉原本經由高頻電刺激所增加的細胞膜表面GluR1次體增加情形。

而在第二部份的研究中，我們進一步探討DCS促進恐懼記憶消除的詳細機制。首先在杏仁核區域腦切片的離體實驗中，我們發現DCS選擇性的增強NMDA受體所調控的突觸反應，但卻不會影響AMPA 受體所調控的突觸反應。低頻電刺激(low-frequency stimulation; LFS)合併給予DCS可誘發GluR1 與GluR2的胞飲作用(endocytosis)產生。原本單獨投予N-methy-D-aspartate (NMDA)無法造成杏仁核區神經細胞產生長期抑制現象(long-term depression ; LTD)與細胞膜表面GluR1與GluR2次體胞飲的濃度，在DCS的合併投予下則可成左熔ㄔ矷C而低頻電刺激(LFS)合併給予DCS所促進的去增益現象與受體胞飲則會在蛋白體抑制劑(proteasome inhibitors)的給予下逆轉。此外，蛋白體抑制劑同樣可逆轉低頻電刺激合併投予DCS 所造成的整體PSD-95與SAP97的減少。接著在活體實驗中，原本在大鼠杏仁核腦區投予DCS所造成的恐懼記憶進一步的消除與細胞膜表面GluR1與GluR2次體的降低也可在蛋白體抑制劑的投予之下達到逆轉。且DCS促進原本興奮性恐懼記憶擦除的部分並不會產生再復發(reinstatement)的行為。

最後在第三部份的研究中，我們探討glycine transporter (GlyT) 抑制劑NFPS對於恐懼記憶消除之分子機制與行為層面上之影響。在杏仁核區域腦切片的離體實驗中，我們發現NFPS選擇性的增強NMDA受體所調控的突觸反應，但卻不會影響AMPA 受體所調控的突觸反應。在GlyT抑制劑NFPS的投予下，會促使原本單獨投予無反應的NMDA產生整體PSD-95與SAP97蛋白質，以及細胞膜表面AMPA受體GluR1與GluR2次體的降低。在活體實驗中，恐懼記憶消除訓練降低了恐懼指數，但卻不會影響經由制約學習所引發的細胞表面GluR1與GluR2次體的增加，但若合併投予NFPS則進一步的加強了記憶的消除反應並只展現出部分的再復發行為，且成左滌f轉了經由制約學習所引發的細胞表面GluR1與GluR2次體的增加，與AMPA/NMDA ratio的上升。最後，恐懼記憶消除訓練合併投予NFPS與Tat-GluR23Y合成胜（已知可阻斷AMPA受體胞飲反應）卻僅僅抑制了恐懼記憶消除訓練合併投予NFPS所造成的額外記憶消除。

綜合以上結果，我們證實了：
1. 恐懼制約與記憶消除訓練模式的執行時間間隔決定了記憶存在的完整性抑或被消除，而DCS可以刺激代表恐懼記憶的興奮性痕跡之逆轉，且DCS所增強的記憶消除與逆轉突觸表面AMPA受體GluR1次體增加情形可能是透過刺激AMPA受體的胞飲作用而產生。
2. DCS所增強的記憶消除與逆轉突觸表面AMPA受體GluR1與GluR2次體增加情形可能是透過刺激AMPA受體的胞飲作用而產生，而此種作用可能與泛蛋白-蛋白體系統(ubiquitin-proteasome system)的調控有關。
3. 恐懼記憶消除訓練合併投予NFPS藉由逆轉GluR1與GluR2次體的細胞膜表現，進而加強了恐懼記憶的消除，而Tat-GluR23Y合成胜專一性的阻斷了NFPS所促進的記憶消除，證實了NFPS所促進的記憶消除與逆轉細胞膜表面AMPA受體GluR1與GluR2次體增加情形可能是由於AMPA受體的胞飲作用而產生。

Exposure-based psychotherapy is a kind of treatment for cognitive behavior. It means that make patients expose to different kinds of stimulating situation, and make them overcome gradually. It is the most common behavioral therapy for anxiety disorders such as posttraumatic stress disorder, social panic and obsessive-compulsive disorder. The overwhelming majority of the treatment for anxiety disorders can adopt the exposure therapy. Patients are exposed to stimulation related to the emotional response step by step, and previously acquired responses will gradually decline.

Much evidence indicates that extinction training does not erase memory traces but forms an inhibitory learning that prevents the expression of original memory. It still remained to be determined whether NMDA-mediated facilitation of extinction is mediated by the enhancement of inhibitory memory and/or the partial erasure of the original memory. Here we investigate the effect of glycine modulatory site on NMDA receptor using NMDA receptor partial agonist (D-cycloserine) and glycine transporter blockers (NFPS) on the conditioning and extinction of fear memory assessed by fear-potentiated startle.

The thesis is divided into 3 parts. In the first part, we investigated the molecular mechanism underlying the effect of the partial agonist D-cycloserine (DCS) at the glycine modulatory site of NMDA receptor on the extinction of fear. Extinction training applied 1 h after training reversed the conditioning-induced increase in surface GluR1 in parallel with the inhibition of startle potentiation. However, if applied 24 h after training, extinction training reduced startle potentiation without influencing GluR1 increase. We infused DCS, a partial agonist of the glycine site on the NMDA receptor, bilaterally into the amygdala 30 min before extinction training. This augmented the extinction training-elicited reduction of startle and reversed the conditioning-induced increase in GluR1. Delivery of five sets of tetanic stimulation (TS) to the external capsule (EC) produced a robust enhancement of synaptic responses in the LA neurons that persisted for more than 2 h. Low-frequency stimulation (LFS) applied at 1 h after TS had no long-lasting effect on synaptic responses. The same treatments however induced depotentiation in the presence of DCS and reversed TS-induced increase in surface GluR1.

In the second part, we further investigated the underlying mechanism of DCS on the extinction of fear memory. In the in vitro experiments on the amygdalar slice, DCS selectively increased NMDA receptor-mediated synaptic response without affecting AMPA receptor-mediated synaptic response. Low-frequency stimulation (LFS) when applied in the presence of DCS induced GluR1 and GluR2 internalization in the amygdala slices. N-methyl-D-aspartate (NMDA) at 10 M that normally was ineffective at inducing long-term depression (LTD) and reducing surface expression of GluR1 and GluR2 succeeded in the presence of DCS. Simultaneously, LFS in combination with DCS increased the level of depotentiation and receptor internalization, which was abolished by proteasome inhibitors. Furthermore, DCS in combination with LFS reduced cellular levels of PSD-95 and synapse-associated protein 97 (SAP97) that were also blocked by proteasome inhibitors. In the in vivo animal experiments, DCS-induced further reduction of fear-potentiated startle and reversal of conditioning-induced increase in surface expression of GluR1 and GluR2 were blocked by proteasome inhibitors. Finally, DCS-treated rats exhibit partial reinstatement after US alone presentations.

In the last part, we investigated the molecular and behavioral effect of glycine transporter blockers (NFPS) on the extinction of fear memory. In the in vitro experiments on the amygdalar slice, NFPS selectively increased NMDA receptor- mediated synaptic response without affecting AMPA receptor-mediated synaptic response. NMDA at a concentration that normally was without effect reduced cellular levels of PSD-95 and SAP97, and the surface expression of GluR1 and GluR2 in the presence of NFPS. In the in vivo animal experiments, Extinction training reduced startle potentiation without influencing conditioning-induced increase in surface expression of GluR1 and GluR2. However, NFPS treatment in conjunction with extinction training augmented extinction and exhibit only partial reinstatement after US alone presentations. Also, it reverse conditioning-induced increase in GluR1 and GluR2 as well as AMPA/NMDA ratio. Finally, Tat-GluR23Y, a synthetic peptide which has been shown to block AMPA receptor endocytosis, inhibited only the additional reduction caused by NFPS treatment.

Taken together, these study have three important findings:
1. Whether a memory trace remains intact or is erased depends on the interval between conditioning and extinction training, and DCS facilitates the reversal of memory trace. DCS-induced augmentation of extinction and reversal of GluR1 surface expression are likely mediated by DCS-facilitated endocytosis of AMPA receptors.
2. DCS facilitates GluR1 and GluR2 internalization in the presence of extinction training resulting in augmented reduction of startle potentiation and these effects are regulated by ubiquitin-proteasome system.
3. NFPS in combination with extinction training reverses GluR1 and GluR2 surface expression and thus augments extinction of conditioned fear, and Tat-GluR23Y specifically blocks the effect of NFPS on the extinction. These results suggest that NFPS-induced augmentation of extinction and reversal of GluR1 and GluR2 surface expression are likely mediated by NFPS-facilitated endocytosis of AMPA receptors.

Ahmadian G, Ju W, Liu L, Wyszynski M, Lee SH, Dunah AW (2004) Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD. EMBO J 23: 1040-1050.
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Fourth Edition
Anderson KC, Insel TR (2006) The promise of extinction research for the prevention and treatment of anxiety disorders. Biol Psychiatry 60: 319-321.
Applegate CD, Frysinger RC, Kapp BS, Gallagher M (1982) Multiple unit activity recorded from amygdala central nucleus during Pavlovian heart rate conditioning in rabbit. Brain Res 238: 457-462.
Aragon C, Lopez-Corcuera B (2003) Structure, function and regulation of glycine neurotransporters. Eur J Pharmacol 47: 249-262.
Aroniadou-Anderjaska V, Post RM, Rogawski MA, Li H (2001) Input-specific LTP and depotentiation in the basolateral amygdala. NeuroReport 12: 635-640.
Atkinson BN, Bell SC, De Vivo M, Kowalski LR, Sechner SM, Ognyanov VI, Tham C-S, Tsai C, Jia J, Ashton D, Klitenick MA (2001) ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter. Mol Pharmacol 60: 1414-1420.
Aubrey KR, Vandenberg RJ (2001) N[3-(4'-Fluorophenyl)-3-(4'-phenylphenoxy) propyl]sarcosine (NFPS) is a selective persistent inhibitor of glycine transport. Br J Pharmacol 134: 1429-1436.
Barad M (2005) Fear extinction in rodents: basic insight to clinical promise. Curr Opin Neurobiol 15: 710-715.
Barad M (2006) Is extinction of fear erasure or inhibition? Why both, of course. Learn Mem 13: 108-109.
Barrionuevo G., Schottler F, Lynch G. 1980. The effect of repetitive low frequency stimulation on control and ‘potentiated’ synaptic responses in the hippocampus. Life Sci 27: 2385-2391.
Bashir ZI, Alford S, Davies SN, Randall AD, Collingridge GL (1991) Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus. Nature 349: 156-158.
Beattie EC, Carroll RC, Yu X, Morishita W, Yasuda H, von Zastrow M, Malenka RC (2000) Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nat Neurosci 3: 1291-1300.
Beique JC, Andrade R (2003) PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex. J Physiol 546: 859-867.
Bellone C, Lscher C (2006) Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat Neurosci 9: 636-641.
Berg WK, Davis M (1985) Associative learning modifies startle reflexes at the lateral lemniscus. Behav Neurosci 99: 191-199.
Bergeron R, Meyer TM, Coyle JT, Greene RW (1998) Modulation of N-methyl-D- aspartate receptor function by glycine transport. Proc Natl Acad Sci USA 95: 15730-15734.
Berman DE, Dudai Y (2001) Memory extinction, learning anew, and learning the new: dissociations in the molecular machinery of learning in cortex. Science 23: 2417-2419.
Billard JM, Rouaud E (2007) Deficit of NMDA receptor activation in CA1 hippocampal area of aged rats is rescued by D-cycloserine. Eur J Neurosci 25: 2260-2268.
Bingol B, Schuman EM (2004) A proteasome-sensitive connection between PSD-95 and GluR1 endocytosis. Neuropharmacology 47: 755-763.
Bingol B, Schuman EM (2005) Synaptic protein degradation by the ubiquitin proteasome system. Curr Opin Neurobiol 15: 536-541.
Bouton ME, Bolles RC (1979) Contextual control of the extinction of conditioned fear. Learn Motiv 10: 445-466.
Bouton ME, King DA (1983) Contextual control of the extinction of conditioned fear: Tests for the associative value of the context. J Exp Psychol Anim Behav Process 9: 248-265.
Bouton ME, Peck CA (1989) Spontaneous recovery in cross-motivational transfer (counterconditioning). Anim Learning Behav 20: 313-321.
Brebner K, Wong TP, Liu L, Liu Y, Campsall P, Gray S (2005) Nucleus accumbens long-term depression and the expression of behavioral sensitization. Science 310: 1340-1343.
Bremner JD (2003) Functional neuroanatomical correlates of traumatic stress revisited 7 years later, this time with data. Psychopharmacol Bull 37: 6-25.
Burbea M, Dreier L, Dittman JS, Grunwald ME, and Kaplan JM (2002) Ubiquitin and AP180 regulate the abundance of GLR-1 glutamate receptors at postsynaptic elements in C. elegans. Neuron 35: 107-120.
Cai C, Coleman SK, Niemi K, Keinanen K (2002) Selective binding of synapse-associated protein 97 to GluR-A alpha-amino-5-hydroxy-3-methyl-4- isoxazole propionate receptor subunit is determined by a novel sequence motif. J Biol Chem 277: 31484-31490.
Cain CK, Godsil BP, Jami S, Barad M (2005) L-type calcium channel blocker nifedipine impairs extinction, but not reduced contingency effects, in mice. Learn Mem 12: 277-284.
Cao TT, Mays RW, von Zastrow M (1998) Regulated endocytosis of G-protein-coupled receptors by a biochemically and functionally distinct subpopulation of clathrin-coated pits. J Biol Chem 273: 24592-24602.
Chain DG, Casadio A, Schacher S, Hegde AH, Valbrun M, Yamamoto N, Goldberg AL, Bartsch D, Kandel ER, Schwartz JH (1999) Mechanisms for generating the autonomous cAMP-dependent protein kinase required for long-term facilitation in Aplysia. Neuron 22: 147-156.
Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408: 936-943.
Chen X, Garelick MG., Wang H, Li V, Athos J, Storm D (2005) PI3 kinase signaling is required for retrieval and extinction of contextual memory. Nature Neurosci 8: 925-931.
Chhatwal JP, Myers KM, Ressler KJ, Davis M (2005) Regulation of gephyrin and GABAA receptor binding within the amygdala after fear acquisition and extinction. J Neurosci 25: 502-506.
Clarkson P and Pokorny M (1995) Handbook of Psychotherapy London and New York.　
Clem RL, Barth A (2006) Pathway-specific trafficking of native AMPARs by in vivo experience. Neuron 49: 663-670.
Colledge M, Dean RA, Scott GK, Langeberg LK, Huganir RL, Scott JD (2000) Targeting of PKA to glutamate receptors through a MAGUK-AKAP complex. Neuron 27: 107-119.
Colledge M, Snyder EM, Crozier RA, Soderling JA, Jin Y, Langeberg LK, Lu H, Bear MF, Scott JD (2003) Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 40: 595-607.
Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26: 365-384.
Coyle JT, Tsai G (2004) The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology 174: 32-28.
Coyle JT, Tsai G, Goff D (2003) Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann N Y Acad Sci 1003: 318-327.
Dalton GL, Wang YT, Floresco SB and Phillips AG (2008) Disruption of AMPA receptor endocytosis impairs the extinction, but not acquisition of learned fear. Neuropsychopharmacology (In press)
Danysz W, ParsonsAC (1998) Glycine and N-methyl-D-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol Rev 50: 597-664.
Davis M, Falls WA, Gewirtz J (2000) Neural systems involved in fear inhibition: extinction and conditioned inhibition. In: Contemporary issues in modeling psychopathology (Myslobodsky M, Weiner I, eds), pp 113-142. Boston: Kluwer Academic.
Davis M, Ressler K, Rothbaum BO, Richardson R (2006) Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry 60: 369-375.
DiAntonio A, Haghighi AP, Portman SL, Lee JD, Amaranto AM, Goodman CS (2001) Ubiquitination-dependent mechanisms regulate synaptic growth and function. Nature 412: 449-452.
Du J, Creson TK, Wu LJ, Ren M, Gray NA, Falke C, Wei Y, Wang Y, Blumenthal R, Machado-Vieira R, Yuan P, Chen G, Zhuo M, Manji HK (2008) The role of hippocampal GluR1 and GluR2 receptors in manic-like behavior. J Neurosci 28: 68-79.
Duvarci S, Nader K (2004) Characterization of fear memory reconsolidation. J Neurosci 24: 9269-9275.
Ehlers MD (2000) Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28: 511-525.
Ehlers MD (2003) Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci 10: 10.
El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS (2000) PSD-95 involvement in maturation of excitatory synapses. Science 290: 1364-1368.
El-Husseini Ael D, Schnell E, Dakoji S, Sweeney N, Zhou Q, Prange O, Gauthier-Campbell C, Aguilera-Moreno A, Nicoll RA, Bredt DS (2002) Synaptic strength regulated by palmitate cycling on PSD-95. Cell 108: 849-863.
Faber ES, Callister RJ, Sah P (2001) Morphological and electrophysiological properties of principal neurons in the rat lateral amygdala in vitro. J Neurophysiol 85: 714-723.
Falls WA, Miserendino JD, Davis M (1992) Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala. J Neurosci 12: 854-863.
Fonseca R, Vabulas RM, Ulrich Hartl F, Bonhoeffer T, Valentin Nagerl U (2006) A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP. Neuron 52: 239-245.
Gadea A, Lopez-Colome AM (2001) Glial transporters for glutamate, glycine, and GABA III. Glycine transporters. J Neurosci Res 64: 218-222.
Goff DC, Coyle RJ (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 158: 1367-1368.
Hampson DR, Huang XP, Oberdorfer MD, Goh JW, Auyeung A, Wenthold RJ (1992) Localization of AMPA receptors in the hippocampus and cerebellum of the rat using an anti-receptor monoclonal antibody. Neuroscience 50: 11-22.
Harsing LG Jr, Juranyi Z, Gacsalyi Tapolcsanyi P, Czompa A, Matyus P (2006) Glycine transporter type-1 and its inhibitors. Curr Med Chem 13: 1017-1044.
Hegde AN, DiAntonio A (2002) Ubiquitin and the synapse. Nat Rev Neurosci 3: 854-861.
Heresco-Levy U (2005) Glutamatergic neurotransmission modulators as emerging new drugs for schizophrenia. Expert Opin Emerg Drugs 10: 827-844.
Heresco-Levy U, Javitt DC, Ebstein R (2005) D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 57: 577-585.
Hermans D, Craske MG, Mineka S, Lovibond PF (2006) Extinction in human fear conditioning. Biol Psychiatry 60: 361-368.
Herry C, Garcia R (2002) Prefrontal cortex long-term potentiation, but not long-term depression, is associated with the maintenance of extinction of learned fear in mice. J Neurosci 22: 577-583.
Heynen AJ, Quinlan EM, Bae DC, Bear MF (2000) Bidirectional, activity-dependent regulation of glutamate receptors in the adult hippocampus in vivo. Neuron 28: 527-536.
Hirai H, Kirsch J, Laube B, Betz H, Kuhse J (1996) The glycine binding site of the N-methyl-D-aspartate receptor subunit NR1: identification of novel determinants of co-agonist potentiation in the extracellular M3–M4 loop region. Proc Natl Acad Sci USA 93: 6031-6036.
Hofmann SG, Meuret AE, Smits AJ, Simon NM, Pollack MH, Eisenmenger K, Shiekh M; Otto MW (2006) Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch Gen Psychiatry 63: 298-304.
Hollingsworth EB, McNeal ET, Burton JL, Williams RJ, Daly JW, Creveling CR (1985) Biochemical characterization of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: cyclic adenosine 3’,5’-monophosphate- generating systems, receptors, and enzymes. J Neurosci 5: 2240-2253.
Javitt DC (2006) Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry 19: 151-157.
Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325: 529-531.
Karasawa J, Hashimoto K, Chaki S (2008) D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats. Behav Brain Res 186: 78-83.
Kelly A, Lynch MA (2000) Long-term potentiation in dentate gyrus of the rat is inhibited by the phosphoinositide 3-kinase inhibitor, wortmannin. Neuropharmacology 39: 643-651.
Kinney GG, Sur C, Burno M, Mallorga PJ, Williams JB, Figueroa DJ, et al. (2003) The glycine transporter type 1 inhibitor N-[3-(4’-fluorophenyl)-3-(4’- phenylphenoxy)propyl]sarcosine potentiate NMDA receptor-mediated response in vivo and produces an antipsychotic profile in rodent behavior. J Neurosci 23: 7586-7591.
Kim J, Lee S, Park K, Hong I, Song B, Son G, Park H, Kim WR, Park E, Choe HK, Kim H, Lee C, Sun W, Kim K, Shin KS, Choi S (2007) Amygdala depotentiation and fear extinction. Proc Natl Acad Sci USA 104: 20955-20960.
Kourrich S, Rothwell PE, Klug JR, Thomas MJ (2007) Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens. J Neurosci 27: 7921-7928.
Lane HY, Chang YC, Liu YC, Chiu, CC, Tsai GE (2005) Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized double blind placebo-controlled study. Arch Gen Psychiatry 62: 1196-1204.
Laube B, Hirai H, Sturgess M, Bet ZH, Kuhse J (1997) Molecular determinants of agonist discrimination by NMDAreceptor subunits: analysis of the glutamate binding site on the NR2B subunit. Neuron 18: 493-503.
Ledgerwood L, Richardson R, Cranney J (2003) Effects of D-cycleserine on the extinction of conditioned freezing. Behav Neurosci 117: 341-349.
Ledgerwood L, Richardson R, Cranney J (2004) D-cycleserine and the facilitation of extinction of conditioned fear: consequences for reinstatement. Behav Neurosci 118: 505-513.
LeDoux JE (2000) The amygdala and emotion: a view through fear. In: The amygdala: a functional analysis (Aggleton JP, ed), pp 289-310. Oxford: Oxford University Press.
Lee H, Kim JJ (1998) Amygdalar NMDA receptors are critical for new fear learning in previously fear-conditioned rats. J Neurosci 18: 8444-8454.
Lee HK, Kameyama K, Huganir RL, Bear MF (1998) NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21: 1151-1162.
Leonard AS, Davare MA, Horne MC, Garner CC, Hell JW (1998) SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit. J Biol Chem 273: 19518-19524.
Liang F, Huganir RL (2001) Coupling of agonist-induced AMPA receptor internalization with receptor recycling. J Neurochem 77: 1626-1631.
Likhtik E, Pelletier JG, Paz R, Par D (2005) Prefrontal control of the amygdala. J Neurosci 25: 7429-7437.
Lin CH, Yeh HW, Lin CH, Lu KT, Leu TH, Chang WC, Gean PW (2001) A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron 31: 841-851.
Lin CH, Yeh SH, Gean PW (2003) The similarities and diversities of signal pathways leading to consolidation and extinction of fear memory. J Neurosci 23: 8310-8317.
Lin JW, Ju W, Foster K, Lee HS, Ahmadian G, Wyszynski M, Wang YT, Sheng M (2000) Distinct molecular mechanismsand divergent endocytotic pathways of AMPA receptor internalization. Nat Neurosci 3: 1282-1290.
Lopez-Salon M, Alonso M, Vianna MRM, Viola H, Mello e Souza T, Izquierdo I, Pasquini J M, Medina J H (2001) The ubiquitin-proteasome cascade is required for mammalian long-term memory formation. Eur J Neurosci 14: 1820-1826.
Man HY, Sekine-Aizawa Y, Huganir RL (2007) Regulation of {alpha}-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking through PKA phosphorylation of the Glu receptor 1 subunit. Proc Natl Acad Sci USA 104: 3579-3584.
Mao SC, Hsiao YH, Gean PW (2006) Extinction training in conjunction with a partial agonist of the glycine site on the NMDA receptor erases memory trace. J Neurosci 26: 8892-8899.
Maren S, Aharonov G, Stote D, Fanselow M (1996) N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats. Behav Neurosci 110: 1365-1374.
Maren S. (2000) Auditory fear conditioning increases CS-elicited spike firing in lateral amygdala neurons even after extensive overtraining. Eur J Neurosci 12: 4047-4054.
Maren S, Quirk GJ (2004) Neuronal signalling of fear memory. Nat Rev Neurosci 5: 844-852.
McBain CJ, Kleckner NW, Wyrick S, Dingledine R (1989) Structural requirements for activation of the glycine coagonist site of N-methyl-D-aspartate receptors expressed in xenopus oocytes. Mol Pharmacol 36: 556-565.
McKernan MG and Shinnick-Gallagher P (1997) Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390: 607-610.
Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420: 70-74.
Millan MJ. N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives (2005) Psychopharmacology 179: 30-53.
Moita MA, Lamprecht R, Nader K, LeDoux JL (2002) A-kinase anchoring proteins in amygdala are involved in auditory fear memory. Nat Neurosci 5: 837-838.
Murphey RK, Godenschwege TA (2002) New roles for ubiquitin in the assembly and function of neuronal circuits. Neuron 36: 5-8.
Myers KM, Davis M (2002) Behavioral and neural analysis of extinction. Neuron 36: 567-584.
Myers KM, Ressler KJ, Davis M (2006) Different mechanisms of fear extinction dependent on length of time since fear acquisition. Learn Mem 13: 216-223.
Nader K, Schafe GE, LeDoux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406: 722-726.
Nakagawa T, Futai K, Lashuel HA, Lo I, Okamoto K, Walz T, Hayashi Y, Sheng M (2004) Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions. Neuron 44: 453-467.
National Institutes of Health NIH Publication No. 06-3879.
Opazo P, Watabe AM, Grant SGN, O'Dell TJ (2003) Phosphatidylinositol 3-kinase regulates the induction of long-term potentiation through extracellular signal-related kinase-independent mechanisms. J Neurosci 23: 3679-3688.
Patrick GN, Bingol B, Weld HA, Schuman EM (2003) Ubiquitin-mediated proteasome activity is required for agonist-induced endocytosis of GluRs. Current Biol 13: 2073-2081.
Pavlov IP (1927) Conditioned reflex: an investigation of the physiological activity of the cerebral cortex. London: Oxford University Press.
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. New York: Academic Press
Pitman RK, Shin LM, Rauch SL (2001) Investigating the patjhogenesis of posttraumatic stress disorder with neuroimaging. J Clin Psychiatry 62: Supp 17: 47-54.
Poyatos I, Ponce J, Aragon C, Gimenez C, Zafra F (1997) The glycine transporter GLYT2 is a reliable marker for glycine-immunoreactive neurons. Brain Res Mol Brain Res 49: 63-70.
Quirk GJ, Garcia R, Gonzlez-Lima F (2006) Prefrontal mechanisms in extinction of conditioned fear. Biol Psychiatry 60: 337-343.
Quirk GJ, Likhtik E, Pelletier JG, Par D (2003) Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J Neurosci 23: 8800-8807.
Quirk GJ, Russo GK, Barron JL, Lebron K (2000) The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci 20: 6225-6231.
Raiteri L, Stigliani S, Siri A, Passalacqua M, Melloni E, Raiteri M, Bonanno G (2005) Glycine taken up through GlyT1 and GlyT2 heterotransporters into glutamatergic axon terminals of mouse spinal cord elicits release of glutamate by homotransporter reversal and through anion channels. Biochem Pharmacol 69: 159-168.
Rescorla RA (2001) Experimental extinction. In: Handbook of contemporary learning theories (Mowrer RR, Klein S ed), pp 119-154. Mahwah NJ: Erlbaum
Rescorla RA, Heth CD (1975) Reinstatement of fear to an extinguished conditioned stimulus. J Exp Psychol Anim Behav Process 1: 88-96.
Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E (2004) Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 61: 1136-1144.
Ressler KJ, Mayberg HS (2007) Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat Neurosci 10: 1116-1124.
Richardson R, Ledgerwood L, Cranney J (2004) Facilitation of fear extinction by D-cycloserine theoretical and clinical implications. Learn Mem 11: 510-516.
Rogan MT, Leon KS, Perez DL, Kandel ER (2005) Distinct neural signatures for safety and danger in the amygdala and striatum of the mouse. Neuron 46: 309-329.
Rogan MT, Staubli UV, LeDoux JE (1997) Fear conditioning induces associative long-term potentiation in the amygdala. Nature 390: 604-607.
Roux MJ, Supplisson S (2000) Neuronal and glial glycine transporters have different stoichiometries. Neuron 25: 373-383.
Royer S, Par D (2002) Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses. Neuroscience 115: 455-462.
Rumbaugh G, Sia GM, Garner CC, Huganir RL (2003) Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons. J Neurosci 23: 4567-4576.
Rumpel S, LeDoux J, Zador A, Malinow R (2005) Postsynaptic receptor trafficking underlying a form of associative learning. Science 308: 83-88.
Sanna PP, Cammalleri M, Berton F, Simpson C, Lutjens R, Bloom FE, Francesconi W
(2002) Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region. J Neurosci 22: 3359-3365.
Schluter OM, Xu W, Malenka RC (2006) Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function. Neuron 51: 99-111.
Schnell E, Sizemore M, Karimzadegan S, Chen L, Bredt DS, Nicoll RA (2002) Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc Natl Acad Sci USA 99: 13902-13907.
Sheng M, Lee SH (2003) AMPA receptor trafficking and synaptic plasticity: major unanswered questions. Neurosci Res 46: 127-134.
Shi S, Hayashi Y, Esteban JA, Malinow R (2001) Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105: 331-343.
Shi SH, Hayashi Y, Petralia RS, Zaman SH, Wenthold RJ, Svoboda K, Malinow R (1999) Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284: 1811-1816.
Sotres-Bayon F, Bush DE, LeDoux JE (2004) Emotional perseveration: an update on prefrontal-amygdala interactions in fear extinction. Learn Mem 11: 525-535.
Speese SD, Trotta N, Rodesch CK, Aravamudan B, Broadie K (2003) The ubiquitin proteasome system acutely regulates presynaptic protein turnover and synaptic efficacy. Curr Biol 13: 899-910.
Stahl SM. Essential Psychopharmacology 3rd ed. New York, NY: Cambridge University Press. (In press)
Staubli U, Chun D (1996) Factors regulating the reversibility of long-term potentiation. J Neurosci 16: 853-860.
Sur C, Kinney GG (2004) The therapeutic potential of glycine transporter-1 inhibitors. Expert Opin Investig Drugs 13: 515-521.
Suzuki, A., Josselyn, S.A., Frankland, P.W., Masushige, S., Silva, A.J., and Kida, S. 2004. Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci 24: 4787-4795.
Tamminga CA, Holcomb HH, Gao XM, Lahti AC (1995) Glutamate pharmacology and the treatment of schizophrenia: current status and future directions. Int Clin Psychopharmacol 3: 29-37.
Taylor S, Thordarson DS, Maxfield L, Fedoroff IC, Lovell K, Ogrodniczuk J (2003) Comparative efficacy, speed, and adverse effects of three PTSD treatments: exposure therapy, EMDR, and relaxation training. J Consult Psychol 71: 330-338.
Thomson AM, Walker VE, Flynn DM (1989) Glycine enhances NMDA receptor-mediated synaptic potentials in neocortical slices. Nature 338: 422-424.
Tomita S, Chen L, Kawasaki Y, Petralia RS, Wenthold RJ, Nicoll RA, Bredt DS (2003) Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins. J Cell Biol 161: 805-816.
Tsai G, Lane HY, Yang P, Chong MY, Lange N (2004) Glycine transporter 1 inhibitor, N-methylglycine (sarcosine) added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 55: 452-456.
Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411: 583-587.
Upadhya SC, Ding L, Smith TK, Hegde AN (2006) Differential regulation of proteasome activity in the nucleus and the synaptic terminals. Neurochem Int 48: 296-305.
Upadhya SC, Smith TK, Hegde AN (2004) Ubiquitin-proteasome mediated CREB repressor degradation during induction of long-term facilitation. J Neurochem 91: 210-219.
Vandenberghe W, Nicoll RA, Bredt DS (2005) Interaction with the unfolded protein response reveals a role for stargazin in biosynthetic AMPA receptor transport. J Neurosci 25: 1095-1102.
Walker DL, Ressler KJ, Lu KT, Davis M (2002) Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci 22: 2343-2351.
Westergren I, Nystrom B, Hamberger A, Nordborg AC, Johansson BB (1994) Concentrations of amino acids in extracellular fluid after opening of the blood-brain barrier by intracarotid infusion of protamine sulfate. J Neurochem 62: 159-165.
Wright CI, Fischer H, Whalen PJ, McInemey SC, Shin LM, Raugh SL (2001) Differential prefrontal cortex and amygdale habituation to repeatedly presented emotional stimuli. NeuroReport 12: 379-383.
Yaka R, Biegon A, Grigoriadis N, Simeonidou C, Grigoriadis S, Alexandrovich AG, Matzner H, Schumann J, Trembovler V, Tsenter J, Shohami E (2007) D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury. FASEB J 21: 2033-2041.
Yang YL, Lu KT (2005) Facilitation of conditioned fear extinction by D-cycloserine is mediated by mitogen-activated protein kinase and phosphoinositol-3-kinase cascades and requires de novo protein synthesis in basolateral nucleus of amygdala. Neuroscience 134: 247-260.
Yeh SH, Mao SC, Lin HC, Gean PW (2006) Synaptic expression of glutamate receptor after encoding of fear memory in the rat amygdale. Mol Pharmacol 69: 299-308.
Yehuda R (2002) Post-traumatic stress disorder. N Eng J Med 346: 108-114.
Zafra F, Gomeza J, Olivares L, Aragon C, and Gimenez C (1995) Regional distribution and developmental variation of the glycine transporters GLYT1 and GLYT2 in the rat CNS. Eur J Neurosci 7: 1342-1352.
Zhao Y, Hegde, AN, Martin, KC (2003) The ubiquitin proteasome system functions as an inhibitory constraint on synaptic strengthening. Cur Biol 13: 887-898.