實驗結果
3. Orexins 影響神經突觸可塑性的機制
(Fig. 6)，暗示突觸前神經訊息傳遞物的釋放受到抑制 (Delaney and Tank, 1994)，但 這個現象在給予[Ala11, D-Leu15] orexin-B 時，並沒有發現。我們的結果暗示 orexin A 在高頻刺激後，可能藉由抑制突觸前神經傳訊物質的釋放來影響突觸可塑性。不
過先前的報導根據在大鼠基礎突觸傳遞的數據認為，orexin A 抑制神經突觸可塑性
並不是經由抑制突觸前神經傳導而來(Aou et al., 2003)。
在研究orexin 於 hippocampus CA1 區域作用的報導中，紛紛指出投予 orexin A 會導致NMDA 電流有下降的趨勢(Aou et al., 2003; Selbach et al., 2004)。再者，本 實驗中利用Theta burst stimulation 所引發的長期增益現象(LTP)恰為 NMDA 受體媒 介所引發為主(Arai et al., 1994; Capocchi et al., 1992)。我們也發現 TBS-LTP 可以受 APV(50 μM) 抑制(data not show)，綜觀上述，我們推測 orexins 所造成的抑制 TBS-LTP 現象，可能是藉由抑制 NMDA 受體所媒介之電流而來。
Orexins 是如何減低 NMDA 電流的原因，目前並不清楚。但我們知道 orexins
可藉由打開 OX1R 打開非選擇性陽離子通道進而增加鈣離子的流入，再活化下游
的PLC/PKC 途徑(Larsson et al., 2005)。同時，高濃度的 orexin A 也可以經由 orexin receptor 而直接活化 PLC/PKC 途徑，不一定需要陽離子通道開啟來活化(Lund et al., 2000)。另一方面，當 NMDA 通道開啟，鈣離子流入時，鈣離子可以活化 calmodulin 來抑制NMDA 通道的開啟(Rosenmund et al., 1995; Wang et al., 2008)。而亦有報導 指出，除了上述作用外，也需Ca2+/calmodulin(Ca2+/CaM) dependent phosphatase 2B (calcineurin)活化來使 NMDA 通道不活化(Lieberman and Mody, 1994; Rycroft and
Gibb, 2004)。並且已知 PKC 會強化 Ca2+/CaM 依賴性之 NMDA 通道不活化(Lu et al., 2000)。但 orexins 減少 NMDA 電流，是否經由 PLC/PKC 及 Ca2+/CaM 途徑，強化
了NMDA 通道不活化狀態，而使得 LTP 的程度弱化，尚有待進一步的實驗證據證
明。
另外一個可能的推測，則是認為orexin 可能藉由影響 NMDA 受體次單位組成 結構比例，而出現抑制長期增益現象(LTP)的程度(Kopp et al., 2006)。首先，我們 知道睡眠剝奪的大鼠體內orexin 濃度會有顯著上升的現象(Pedrazzoli et al., 2004)，
而在另一個實驗中則發現，睡眠剝奪後的大鼠長期增益現象(LTP)有顯著下降的趨 勢，且LTP 下降的現象是由於 NR2A/NR2B 比例變大，即 NR2A 變多所導致(Kopp et al., 2006; Philpot et al., 2003)。由於 orexin 也有被報導會增加 NMDA 受體的表現 (Borgland et al., 2006)，但不知 orexin 在此是否藉改變 NR2A/NR2B 比例，而降低 影響長期增益現象(LTP)的形成，仍有待更進一步研究。
結論
根據我們目前的實驗結果，在小鼠 hippocampus CA1 區域，發現 orexin A 和[Ala11, D-Leu15]-orexin B 皆不影響基礎突觸傳遞，但會抑制 LTP 的程度，而不影響
depotentiation。對 LTP 的抑制效果，可能同時經由 OX1R 和 OX2R，但 OX1R 可 能佔有較大的比重。再者，突觸前的抑制效果可能很輕微，推論主要是在突觸後，
藉由活化OX1R 和 OX2R 及其下游反應所造成。
Hypocretin 1: LGVDAQPLPDCCRQKTCSCRLYELLHGAGNHAAGILTL-amide Orexin A: QPLPDCCRQKTCSCRLYELLHGAGNHAAGILTL-amide Hypocretin 2 : RPGPPGLQGRLQRLLQANGNHAAGILTMG-amide Orexin B: RPGPPGLQGRLQRLLQANGNHAAGILTM-amide Secretin : HSDGTFTSELSRLODSARLQRLLQGLV ＊HSDGTFTSE
Fig. 1 Amino acid seqences of hypocretin- 1( rat and mice), orexin A, hypocretin- 2, orexin B and secretin.
Fig. 2 Schematic drawing of sagittal section through the rat brain to summarize the organization of orexin neuronal system. Dots indicate the relative
location of orexin-immunoreactive neurons, and arrows show some of the more prominent terminal fields. (Adapted from T. Nambu et al., 1999, Brain Research)
Figure 3. Orexin A and orexin B are derived from a common precursor peptide, prepro-orexin. The actions of orexins are mediated via two G protein-coupled receptors named orexin-1 (OX1R) and orexin-2 (OX2R) receptors. OX1R is selective for orexin A, whereas OX2R is a nonselective receptor for both orexin A and orexin B. OX1R is coupled exclusively to the Gq subclass of heterotrimeric G proteins, whereas OX2R couples to Gi/o and/or Gq.(Matsuki and Sakurai, 2008)
(A)
(B)
Fig. 4 Effects of orexins at various concentrations on the fEPSP slopes of Schaffer collateral-CA1 synapses in mouse hippocampal slices. Effects of orexins A (A) or [Ala11, D-Leu15]-orexin B (B) 10 min after application and was expressed as % of averaged baseline fEPSPs, which were taken 10 min before drug application. Data are the mean ± SEM. Slice numbers are denoted in the parentheses.
Fig. 5 Effects of orexin A on synaptic plasticity of hippocampal CA1 synapses.
After fEPSPs evoked at 0.03 Hz (basal stimulation) reached stead state, theta burst stimulation (TBS) (arrow), 3 theta burst trains as described in methods, was given to induced LTP. After TBS, the stimulation frequency was switched back to 0.03Hz and fEPSPs were recorded for 40 min, followed by low frequency stimulation (LFS) (thin horizontal line), 1Hz, 15 min for inducing depotentiation. Orexin A (30, 100,300 nM) were applied (thick horizontal bar) 10 min before TBS. The traces in the upper panel are the average of 4 fEPSPs recorded at the times denoted: a, control baseline fEPSP; b, the baseline fEPSP 10 min after orexin A treatment; c:
the fEPSP 40 min after TBS; d: the fEPSPs 40 min after LFS.
(A) (B)
(C)
Fig. 6 Effects of orexin A on (A)PTP (B)LTP and (C)depotentiation. (A)The slightly dose-related suppression of PTP (21-25 min) by orexin A. however, there are no significant differences between each group. (B)The dose-related suppression of LTP (time 78-80 min) by orexin A (100 and 300 nM). **P<0.01.
Fig. 7A Effect of SB 334867, an OX 1 receptor antagonist, on orexin A-induced alteration of synaptic plasticity. Filed EPSP slopes at the baseline, after treatment with normal ACSF (open circles), 100 nM orexn A (filled circles) or 3 μM SB 334867 alone (filled triangles) and 100 nM orexin A plus 3 μM SB 334867 (filled inverse triangles), after TBS and LFS were shown. Scale bar: vertical 0.1mV, horizontal 10ms
Fig. 7B Effect of SB 334867, an OX 1 receptor antagonist, on orexin A-induced alteration of synaptic plasticity. Statistic bars of the effects of ACSF, orexin A or 3 μM SB 334867 alone, and 100 nM orexin A plus 3 μM SB 334867 on baseline, PTP, LTP and depotentiation.
Fig. 8A Effects of Compound 29, an OX 2 receptor antagonist, on orexin A-induced alteration of synaptic plasticity. Filed EPSP slopes at the baseline, after treatment with normal ACSF (open circles), 100 nM orexn A (filled circles) or 30 μM Compound 29 alone (filled triangles) and 100 nM orexin A plus 30 μM Compound 29 (filled inverse triangles), after HFS and LFS were shown. Scale bar:
vertical 0.1mV, horizontal 10ms
Fig. 8B Effects of Compound 29, an OX 2 receptor antagonist, on orexin A-induced alteration of synaptic plasticity Statistic bars of the effects of ACSF, orexin A or 30 μM Compound 29 alone, and 100 nM orexin A plus 30 μM Compound 29 on baseline, PTP, LTP and depotentiation.
Fig. 9A Effects of [Ala11, D-Leu15]- orexin B (3 ,10, 300nM) on synaptic plasticity of hippocampal CA1 synapses. The stimulation and analysis are the same as Fig. 5.
Scale bar: vertical 0.1mV, horizontal 10ms
Fig. 9B Effects of [Ala11, D-Leu15]- orexin B (100, 300, 1000 nM) on synaptic plasticity of hippocampal CA1 synapses. The stimulation and analysis are the same as Fig. 5. Scale bar: vertical 0.1mV, horizontal 1ms
(A) (B)
(C)
Fig. 10 Effect of [Ala11, D-Leu15]-orexin B on (A)PTP(21-25 min) are no significant differences between each group. (B)The dose-related suppression of LTP (time 78-80 min) by [Ala11, D-Leu15]-orexin B. (C) depotentiation (time 113-115 min) shows no significant difference. *P<0.05
Fig. 11A Effect of SB 334867, an OX 1 receptor antagonist, on [Ala11, D-Leu15]-orexin B -induced alteration of synaptic plasticity. Filed EPSP slopes at the baseline, after treatment with normal ACSF (open circles), 300 nM [Ala11, D-Leu15]-orexin B (filled circles) or 3 μM SB 334867 alone (filled triangles) and 300 nM [Ala11, D-Leu15]-orexin B plus 3 μM SB 334867 (filled inverse triangles), after TBS and LFS were shown. Scale bar: vertical 0.1mV, horizontal 1ms
Fig. 11B Effect of SB 334867, an OX 1 receptor antagonist, on [Ala11, D-Leu15]-orexin B-induced alteration of synaptic plasticity. Statistic bars of the effects of ACSF, 300 nM [Ala11, D-Leu15]-orexin B or 3 μM SB 334867 alone, and 300 nM [Ala11, D-Leu15]-orexin B plus 3 μM SB 334867 on baseline, PTP, LTP and depotentiation.
Fig. 12A Effects of Compound 29, an OX 2 receptor antagonist, on [Ala11, D-Leu15]-orexin B -induced alteration of synaptic plasticity. Filed EPSP slopes at the baseline, after treatment with normal ACSF (open circles), 300 nM [Ala11, D-Leu15]-orexin B(filled circles) or 30 μM Compound 29 alone (filled triangles) and 300 nM [Ala11, D-Leu15]-orexin B plus 30 μM Compound 29 (filled inverse triangles), after HFS and LFS were shown. Scale bar: vertical 0.1 mV, horizontal 1 ms
Fig. 12B Effects of Compound 29, an OX 2 receptor antagonist, on orexin A-induced alteration of synaptic plasticity Statistic bars of the effects of ACSF, 300 nM [Ala11, D-Leu15]-orexin B or 30 μM Compound 29 alone, and 300 nM [Ala11, D-Leu15]-orexin B A plus 30 μM Compound 29 on baseline, PTP, LTP and depotentiation.
Table 1. putative subtype-selective ligands of orexin receptors
OX1R OX2R
Agonist Orexin A Orexin B
[Ala27] orexin B [Pro11] orexin B [Ala11, D-Leu15] orexin B
Antagonist SB 334867 Compound 29 (N-Acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) (Cheng et al., 2005)
Baseline Drug application LTP Depotentiation Orexin A (nM)
PPR PPR PPR change PPR PPR change PPR PPR change
0 1.62±0.04 (8) 1.60±0.04 0.98±0.02 1.51±0.03 0.93±0.02 1.53±0.05 0.94±0.02 100 1.66±0.1 (5) 1.66±0.03 1.01±0.05 1.62±0.07 0.98±0.03 1.67±0.09 1.01±0.04 300 1.57±0.01 (4) 1.55±0.02 0.98±0.01 1.49±0.04 0.94±0.02 1.57±0.07 0.99±0.05
Trace: a, control baseline fEPSP; b, the baseline fEPSP 10 min after orexin A treatment; c: the fEPSP 40 min after TBS; d: the fEPSPs 40 min after LFS.
Table. 2 Paired pluse ratio (PPR) before and after orexin A application at basal stimulation state, LTP and depotentiation states
Paired pluse ratio of the fEPSPs evoked by paired pluses (50 ms interval) were calculated at the times denoted.
PPR change was obtained from PPR of each group divided by baseline PPR.
There were no statistically significant among each groups.
Table 3. Effect of orexins on learning and memory
↑ Morris water maze
↑ Passive avoidance test rat Intra-CA1 Endogenous orexins* OX1R (Akbari et al., 2008;
Akbari et al., 2007)
↑ Morris water maze
↑ Passive avoidance test rat Intra-DG Endogenous orexins* OX1R (Akbari et al., 2008;
Akbari et al., 2006)
Orexin A induces LTP, no effect of orexin B, on basal
transmission
C57BL/6j
mice CA1 Orexin A (100 nM)
Orexin B (100 nM) OX1R (Selbach et al., 2004)
* Endogenous orexins were revealed by application of SB 334867 (4.7~18.8 nmol)
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