神经甾体硫化孕烯醇酮对大鼠前额叶皮层内侧区长时程增强的作用和机制
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摘要
硫化孕烯醇酮(pregnenolone sulfate，PREGS)是哺乳动物脑内含量最为丰富的神经甾体之一。PREGS在脑内分布相当广泛，参与各种生理或病理生理过程。许多研究表明PREGS对哺乳动物认知功能相关的生理和病理过程都具有明显的调节作用，但其具体机制还不甚清楚。前额叶皮层内侧区是动物脑内高级认知功能的核心区域，其与高级认知的处理及许多精神障碍密切相关。已有研究表明前额叶皮层内侧区的突触可塑性在永久记忆的形成、巩固和再现中起重要作用。而长时程增强(Long-term Potentiation，LTP)是突触可塑性的重要指标之一，被认为是学习记忆等认知功能的细胞分子基础。因此PREGS对前额叶皮层内侧区LTP可能有调节作用，但此假说仍需验证。
本实验就采用离体脑片全细胞膜片钳技术，并结合电刺激和药理学方法，研究了PREGS对前额叶皮层内侧区LTP的作用和机制；进而用行为学方法探讨了其可能的整体功能意义。结果表明：在离体脑片实验中1μM PREGS对单刺激诱发的EPSCs的初始斜率无持续性抑制作用，但可以明显抑制前额叶皮层内侧区强直刺激诱导的LTP；其作用最低浓度为0.3μM，并且随着浓度的增加而增加，到1μM后逐渐达到一个作用平台。PREGS对LTP维持期无明显作用。再次给予强直刺激不能逆转PREGS对LTP的抑制作用。与此相反，1μM PREGS对海马CA1区的LTP无明显抑制作用，而0.3μM PREGS则可显著增强海马CA1区的LTP。这与已有的报道一致。为了阐明PREGS对前额叶皮层内侧区LTP作用的部位，我们研究了PREGS(1μM)对外源性施加NMDA诱发的NMDA电流的作用、以及对LTP诱导过程中双脉冲易化(PPF)的作用。结果表明PREGS对前额叶皮层内侧区外源性施加NMDA诱发的NMDA电流无明显作用，但可明显影响LTP诱导过程中PPF的变化，提示PREGS抑制前额叶皮层内侧区LTP的作用部位可能在突触前，而不在突触后。为了进一步阐明PREGS抑制前额叶皮层内侧区LTP的作用机制，我们研究了不同工具药对PREGS作用的影响。结果表明G_i蛋白抑制剂N-ethylmaleimide(NEM)可以全部取消PREGS对LTP的作用。D2受体拮抗剂haloperidol对PREGS作用无明显影响。而α_2受体拮抗剂yohombine可完全取消PREGS的作用，选择性α_2受体激动剂B-HT 933可完全模拟PREGS的作用。α_(2A)受体拮抗剂BRL-44408可完全逆转PREGS的作用。进一步给予腺苷酸环化酶(AC)抑制剂MDL-12，330A和蛋白激酶A(PKA)抑制剂H89均可全部取消PREGS对LTP的抑制作用。另外，有趣的是当电极内加入H89使其充分扩散到所记录的突触后细胞内，并未对PREGS对LTP的抑制作用产生任何影响，进一步确证了PREGS的作用部位并非突触后。整体行为学实验中，我们在前额叶皮层内侧区双侧局部注射PREGS，进而在水迷宫中检测与前额叶皮层内侧区相关的行为学指标，发现PREGS对大鼠游泳速度无明显影响，但可缩短大鼠寻找平台的时间和路程，从而促进了与前额叶皮层内侧区相关的认知功能。
以上实验结果表明1μM PREGS可通过激活突触前与G_i蛋白偶联的α_(2A)受体，然后通过抑制AC和PKA信号通路，从而对大鼠前额叶皮层内侧区LTP的诱导产生抑制作用，进而对其相关的整体认知功能产生促进作用。
The effect and mechanism of neurosteroid pregnenolone sulfate on long-term potentiation in rat medial prefrontal cortex
Pregnenolone sulfate (PREGS) is one of the most abundantly producedneurosteroids in the brain. PREGS has extensive distribution in the brain and isinvolved in many processes of physiology and pathology. Accumulated evidencesshow that PREGS could regulate many pathophysiological changes concerned withcognition, but the mechanism is not clear. The medial prefrontal cortex is the mainbrain region for higher cognition function, which is involved in the processes ofhigher cognition and many psychiatric disorders. The glutamatergic synaptic plasticityin the medial prefrontal cortex is thought to be important for the establishment,consolidation and retrieval of permanent memory. Long-term potentiation (LTP) isone of the important indications of synaptic plasiticity and regarded as the cellularmechanism of the learning and memory. So, PREGS might have effect on LTP inmedial prefrontal cortex, which needs to be determined by experiment.
The present paper studies the effect and its mechanism of PREGS on LTP in thepyramidal cells of the layersⅤ-Ⅵof the medial prefrontal cortex using whole-cellpatch-clamp with electrical stimulus and pharmacological methods in slices, and thenwe also analyzed its possible function consequence using animal behavior. We foundthat, in brain slices, 1μM PREGS had no consistent effect on the basal slope of singlestimulation evoked EPSCs, but can inhibit distinctly tetanus evoked LTP in medialprefrontal cortex. The effect of PREGS was significant at concentration of 0.3μMand increased with an increase in concentrations and appeared to reach a plateau after1μM. PREGS had no effect on the maintenance of LTP. The second tetanusstimulation could not reverse its inhibitory effect. On the contrary, 1μM PREGS hadno significant influence on the induction of LTP in CA1 pyramidal neurons of thehippocampus, but 0.3μM PREGS enhanced distinctly the LTP. This result wasconsistent with others report. To determine the position of its effect, we studied theeffect of PREGS on the amplitude of NMDA evoked current, the paired-pulsefacilitation (PPF) during the LTP induction. We found that PREGS had no effect onthe amplitude of NMDA currents, but significantly occluded the PPF change duringthe LTP induction. These results indicated PREGS inhibited the induction of LTP inthe medial prefrontal cortex by presynaptic but not postsynaptic function.
To further elucidate the mechanism of the inhibitory effect of PREGS on the induction of LTP, we studied the effect of inhibtors and agonists on the function ofPREGS. We found that the selective G_i protein inhibitor N-ethylmaleimide (NEM)canceled the effect of PREGS on LTP, theα_2 receptor antagonist yohombine andα_2Areceptor antagonist RBL-44408 can also canceled the effect of PREGS, but the D_2receptor antagonist haloperidol did not have influence on the effect of PREGS, theselectiveα_2 receptor agonist B-HT 933 could mimick the effect of PREGS. We alsostudied the downstream pathway of this effect by perfusing with adenylate cyclase(AC) inhibitor MDL-12,330A and protein kinase A (PKA) inhibitor H89. The resultsshown that could also cancel the effect of PREGS on LTP completely. It's interestingthat when we added H89 into the pipette solution and allowed it to be diffused into thepostsynapfic cell, we did not found any influence of H89 on the effect of PREGS onthe LTP. In animal behavior, local injection of PREGS into the medial prefrontalcortex to measure the response learning involved in the medial prefrontal cortex usingMorris Water Maze, we founded that PREGS does not have the effect on theswimming speed, but could decrease the eacape latency and pathway.
In summary, PREGS inhibits the induction of LTP via activation ofα_2A receptorcoupled with G_i protein by presynaptic in rat medial prefrontal cortex. This effect isinvolved in AC-PKA signal pathway, and then may benefit cognition function in vivo.
本实验就采用离体脑片全细胞膜片钳技术，并结合电刺激和药理学方法，研究了PREGS对前额叶皮层内侧区LTP的作用和机制；进而用行为学方法探讨了其可能的整体功能意义。结果表明：在离体脑片实验中1μM PREGS对单刺激诱发的EPSCs的初始斜率无持续性抑制作用，但可以明显抑制前额叶皮层内侧区强直刺激诱导的LTP；其作用最低浓度为0.3μM，并且随着浓度的增加而增加，到1μM后逐渐达到一个作用平台。PREGS对LTP维持期无明显作用。再次给予强直刺激不能逆转PREGS对LTP的抑制作用。与此相反，1μM PREGS对海马CA1区的LTP无明显抑制作用，而0.3μM PREGS则可显著增强海马CA1区的LTP。这与已有的报道一致。为了阐明PREGS对前额叶皮层内侧区LTP作用的部位，我们研究了PREGS(1μM)对外源性施加NMDA诱发的NMDA电流的作用、以及对LTP诱导过程中双脉冲易化(PPF)的作用。结果表明PREGS对前额叶皮层内侧区外源性施加NMDA诱发的NMDA电流无明显作用，但可明显影响LTP诱导过程中PPF的变化，提示PREGS抑制前额叶皮层内侧区LTP的作用部位可能在突触前，而不在突触后。为了进一步阐明PREGS抑制前额叶皮层内侧区LTP的作用机制，我们研究了不同工具药对PREGS作用的影响。结果表明G_i蛋白抑制剂N-ethylmaleimide(NEM)可以全部取消PREGS对LTP的作用。D2受体拮抗剂haloperidol对PREGS作用无明显影响。而α_2受体拮抗剂yohombine可完全取消PREGS的作用，选择性α_2受体激动剂B-HT 933可完全模拟PREGS的作用。α_(2A)受体拮抗剂BRL-44408可完全逆转PREGS的作用。进一步给予腺苷酸环化酶(AC)抑制剂MDL-12，330A和蛋白激酶A(PKA)抑制剂H89均可全部取消PREGS对LTP的抑制作用。另外，有趣的是当电极内加入H89使其充分扩散到所记录的突触后细胞内，并未对PREGS对LTP的抑制作用产生任何影响，进一步确证了PREGS的作用部位并非突触后。整体行为学实验中，我们在前额叶皮层内侧区双侧局部注射PREGS，进而在水迷宫中检测与前额叶皮层内侧区相关的行为学指标，发现PREGS对大鼠游泳速度无明显影响，但可缩短大鼠寻找平台的时间和路程，从而促进了与前额叶皮层内侧区相关的认知功能。
以上实验结果表明1μM PREGS可通过激活突触前与G_i蛋白偶联的α_(2A)受体，然后通过抑制AC和PKA信号通路，从而对大鼠前额叶皮层内侧区LTP的诱导产生抑制作用，进而对其相关的整体认知功能产生促进作用。
The effect and mechanism of neurosteroid pregnenolone sulfate on long-term potentiation in rat medial prefrontal cortex
Pregnenolone sulfate (PREGS) is one of the most abundantly producedneurosteroids in the brain. PREGS has extensive distribution in the brain and isinvolved in many processes of physiology and pathology. Accumulated evidencesshow that PREGS could regulate many pathophysiological changes concerned withcognition, but the mechanism is not clear. The medial prefrontal cortex is the mainbrain region for higher cognition function, which is involved in the processes ofhigher cognition and many psychiatric disorders. The glutamatergic synaptic plasticityin the medial prefrontal cortex is thought to be important for the establishment,consolidation and retrieval of permanent memory. Long-term potentiation (LTP) isone of the important indications of synaptic plasiticity and regarded as the cellularmechanism of the learning and memory. So, PREGS might have effect on LTP inmedial prefrontal cortex, which needs to be determined by experiment.
The present paper studies the effect and its mechanism of PREGS on LTP in thepyramidal cells of the layersⅤ-Ⅵof the medial prefrontal cortex using whole-cellpatch-clamp with electrical stimulus and pharmacological methods in slices, and thenwe also analyzed its possible function consequence using animal behavior. We foundthat, in brain slices, 1μM PREGS had no consistent effect on the basal slope of singlestimulation evoked EPSCs, but can inhibit distinctly tetanus evoked LTP in medialprefrontal cortex. The effect of PREGS was significant at concentration of 0.3μMand increased with an increase in concentrations and appeared to reach a plateau after1μM. PREGS had no effect on the maintenance of LTP. The second tetanusstimulation could not reverse its inhibitory effect. On the contrary, 1μM PREGS hadno significant influence on the induction of LTP in CA1 pyramidal neurons of thehippocampus, but 0.3μM PREGS enhanced distinctly the LTP. This result wasconsistent with others report. To determine the position of its effect, we studied theeffect of PREGS on the amplitude of NMDA evoked current, the paired-pulsefacilitation (PPF) during the LTP induction. We found that PREGS had no effect onthe amplitude of NMDA currents, but significantly occluded the PPF change duringthe LTP induction. These results indicated PREGS inhibited the induction of LTP inthe medial prefrontal cortex by presynaptic but not postsynaptic function.
To further elucidate the mechanism of the inhibitory effect of PREGS on the induction of LTP, we studied the effect of inhibtors and agonists on the function ofPREGS. We found that the selective G_i protein inhibitor N-ethylmaleimide (NEM)canceled the effect of PREGS on LTP, theα_2 receptor antagonist yohombine andα_2Areceptor antagonist RBL-44408 can also canceled the effect of PREGS, but the D_2receptor antagonist haloperidol did not have influence on the effect of PREGS, theselectiveα_2 receptor agonist B-HT 933 could mimick the effect of PREGS. We alsostudied the downstream pathway of this effect by perfusing with adenylate cyclase(AC) inhibitor MDL-12,330A and protein kinase A (PKA) inhibitor H89. The resultsshown that could also cancel the effect of PREGS on LTP completely. It's interestingthat when we added H89 into the pipette solution and allowed it to be diffused into thepostsynapfic cell, we did not found any influence of H89 on the effect of PREGS onthe LTP. In animal behavior, local injection of PREGS into the medial prefrontalcortex to measure the response learning involved in the medial prefrontal cortex usingMorris Water Maze, we founded that PREGS does not have the effect on theswimming speed, but could decrease the eacape latency and pathway.
In summary, PREGS inhibits the induction of LTP via activation ofα_2A receptorcoupled with G_i protein by presynaptic in rat medial prefrontal cortex. This effect isinvolved in AC-PKA signal pathway, and then may benefit cognition function in vivo.
引文
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