去甲肾上腺素对耳蜗螺旋神经元GABA电流的作用
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摘要
目的:
作为听觉传导通路的第一级神经元,螺旋神经元(spiral ganglion neuron)接受来自脑干听觉核团——橄榄耳蜗核的外侧橄榄耳蜗传出系统神经纤维的支配和调控(GABA是其主要神经递质),同时接受来自颈交感神经节(颈上神经节和星状神经节)的纤维支配(Noradrenaline是其主要神经递质),但来自交感系统的纤维对耳蜗SGN电活动的调控机制尚不清楚。本课题主要研究交感纤维神经递质Noradrenaline对GABA在SGN诱发电流的影响及其胞内机制,以探讨交感系统调控SGN电活动进而调控听觉的可能机制。
方法:
1体外培养SGN细胞并进行形态和生理特性鉴定
对出生后0～5d的SD大鼠的螺旋神经节细胞进行酶解分离与培养。用荧光倒置相差显微镜观察培养SGN细胞的活力以及生长与分化过程。应用免疫荧光染色方法对SGN进行免疫细胞化学染色鉴定。建立穿孔膜片钳记录SGN电生理的技术方法并记录SGN基本电生理特性。
2 NA对GABA诱发SGN电流的作用
利用穿孔膜片钳技术,观察去甲肾上腺素(Noradrenaline, NA)对培养SGN GABA诱发电流的作用,以及介导NA调控SGN GABA电流的肾上腺素受体和NA调控SGN GABA电流的胞内分子机制。
结果:
1新生SD大鼠SGN在酶解分离、体外培养条件下,可获得良好的细胞形态及表形分化,表现出稳定的神经元可塑性。本培养条件下细胞可存活7～10d。接种6h后,部分细胞贴壁,有少部分细胞可见小突起,培养12 h后贴壁完成并过渡为极性细胞,l8h后贴壁的SGN细胞多呈椭圆形,胞膜清晰、胞浆匀质、折光性好,胞体透明,周围有明显的光晕。24h后,大多数SGN呈双极神经元形态,胞体两极伸出神经元突起,长的达胞体的4～5倍,短的达胞体的2～4倍。SGN可以直接贴附于多聚赖氨酸基质表面生长,亦可附着在成纤维细胞形成的单层细胞“毯”的表面生长。48～72h后细胞进一步分化,神经细胞突起可为胞体的7～8倍。7d后细胞逐渐退变直至凋亡。除神经细胞外,胶质细胞、雪旺细胞多呈扁平、多角形或长梭形,比神经细胞胞体大,胞膜不清晰,无光晕。NeuN免疫细胞化学染色,SGN全细胞着色,呈绿色,椭圆形胞体和神经突起十分清晰,表明具有神经元的特征。
2 NA可逆性抑制GABA在培养SGN细胞上诱发的电流反应,这种抑制作用具有浓度依赖型,且不影响GABA的反转电位和GABA与其受体的亲和力。α1肾上腺素受体拮抗剂哌唑嗪(Pra),能轻微阻断NA对IGABA的抑制效应,α2肾上腺素受体激动剂可乐定(Clo)和拮抗剂育亨宾(Yoh)能分别模拟和阻断NA对GABA的作用。而β肾上腺素受体激动剂异丙肾上腺素(Iso),不能模拟NA对IGABA的抑制效应。百日咳毒素(IAP)敏感的G蛋白参与了NA对SGN IGABA抑制性调控。NA对SGN IGABA的抑制作用是由蛋白激酶A(PKA)相关的胞内信号转导机制介导的,蛋白激酶A抑制剂H-89能模拟NA对GABA的作用,在加入cAMP和蛋白激酶A激动剂时NA对IGABA的作用消失,但是在加入蛋白激酶C的激动剂PMA和抑制剂白屈菜赤碱(Che)时的,NA仍可抑制SGN IGABA。
结论
1培养新生大鼠SGN细胞的方法可获得良好状态的SGN细胞,SGN存活细胞的数量和周期可以满足体外穿孔膜片钳电生理实验的需要。
2穿孔膜片钳电生理结果表明NA对SGN细胞GABA电流的抑制作用是由α2肾上腺素受体介导的,α2肾上腺素受体激活后可通过抑制腺苷酸环化酶减少胞内cAMP含量,降低PKA活性,进而导致GABA对SGN的抑制作用减弱。表明源于交感系统的NA可通过抑制GABA反应来调控SGN的听觉信息传递。
Aim:
Spiral ganglion neurons (SGNs) in the cochlea receiveγ-aminobutyric acid (GABA)-ergic modulation through the lateral olivocochlear system from the superior olivary complex, and noradrenaline (NA)-ergic innervation from the superior cervical ganglion. But the modulatory effects of NA on GABA-activated responses in the SGNs remain unknown. In the present study, the modulatory effects of NA on the GABA responses were investigated in the isolated cultured SGNs of rat.
Methods:
The culture of SGN was carried out with postnatal day 0～5 SD rats. The process of cellular growth and differentiation of SGN were observed by fluorescent inverted/phase contrast microscope. Immunocytochemical identification was performed on the cultured SGN of SD rats by methods of fluorescence and the antibody of neuron-specific nuclear protein (NeuN). The effect of NA on GABA responses in the SGN was studied by using nystatin perforated patch recording configuration under voltage-clamp conditions. Results:
The trypsin dissociated and cultured SGN of SD rats could survive well and had a normal phenotypic differentiation in vitro. The stable neuronal plasticity of SGN existed in the postnatal SD rats under the present experimental conditions. NA reversibly depressed GABA responses in a concentration-dependent manner and neither changed the reversal potential of the GABA response nor affected the apparent affinity of GABA to its receptor.α2-adrenoceptor agonist and antagonist, clonidine and yohimbine mimicked and blocked the NA action on GABA response, respectively. N-[2(methylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride (H-89), a protein kinase A inhibitor, mimicked the effect of NA on GABA response. NA failed to affect the GABA response in the presence of both cyclic adenosine 5’-monophosphoric acid (cAMP) and protein kinase A modulators. However, NA still depressed the GABA response even in the presence of both phorbol-12-myristate-13-acetate (PMA), a protein kinase C activator and chelerythrine, a protein kinase C inhibitor.
Conclusion:
The cell amount and surviving period of cultured SGN were able to meet the requirements of cytological experiments. NA suppresses GABA response viaα2-adrenoceptor which reduces intracellular cAMP formation through the inhibition of adenyl cyclase. Therefore, NA input to the SGNs may modulate the auditory transmission by affecting the GABA responses.
作为听觉传导通路的第一级神经元,螺旋神经元(spiral ganglion neuron)接受来自脑干听觉核团——橄榄耳蜗核的外侧橄榄耳蜗传出系统神经纤维的支配和调控(GABA是其主要神经递质),同时接受来自颈交感神经节(颈上神经节和星状神经节)的纤维支配(Noradrenaline是其主要神经递质),但来自交感系统的纤维对耳蜗SGN电活动的调控机制尚不清楚。本课题主要研究交感纤维神经递质Noradrenaline对GABA在SGN诱发电流的影响及其胞内机制,以探讨交感系统调控SGN电活动进而调控听觉的可能机制。
方法:
1体外培养SGN细胞并进行形态和生理特性鉴定
对出生后0～5d的SD大鼠的螺旋神经节细胞进行酶解分离与培养。用荧光倒置相差显微镜观察培养SGN细胞的活力以及生长与分化过程。应用免疫荧光染色方法对SGN进行免疫细胞化学染色鉴定。建立穿孔膜片钳记录SGN电生理的技术方法并记录SGN基本电生理特性。
2 NA对GABA诱发SGN电流的作用
利用穿孔膜片钳技术,观察去甲肾上腺素(Noradrenaline, NA)对培养SGN GABA诱发电流的作用,以及介导NA调控SGN GABA电流的肾上腺素受体和NA调控SGN GABA电流的胞内分子机制。
结果:
1新生SD大鼠SGN在酶解分离、体外培养条件下,可获得良好的细胞形态及表形分化,表现出稳定的神经元可塑性。本培养条件下细胞可存活7～10d。接种6h后,部分细胞贴壁,有少部分细胞可见小突起,培养12 h后贴壁完成并过渡为极性细胞,l8h后贴壁的SGN细胞多呈椭圆形,胞膜清晰、胞浆匀质、折光性好,胞体透明,周围有明显的光晕。24h后,大多数SGN呈双极神经元形态,胞体两极伸出神经元突起,长的达胞体的4～5倍,短的达胞体的2～4倍。SGN可以直接贴附于多聚赖氨酸基质表面生长,亦可附着在成纤维细胞形成的单层细胞“毯”的表面生长。48～72h后细胞进一步分化,神经细胞突起可为胞体的7～8倍。7d后细胞逐渐退变直至凋亡。除神经细胞外,胶质细胞、雪旺细胞多呈扁平、多角形或长梭形,比神经细胞胞体大,胞膜不清晰,无光晕。NeuN免疫细胞化学染色,SGN全细胞着色,呈绿色,椭圆形胞体和神经突起十分清晰,表明具有神经元的特征。
2 NA可逆性抑制GABA在培养SGN细胞上诱发的电流反应,这种抑制作用具有浓度依赖型,且不影响GABA的反转电位和GABA与其受体的亲和力。α1肾上腺素受体拮抗剂哌唑嗪(Pra),能轻微阻断NA对IGABA的抑制效应,α2肾上腺素受体激动剂可乐定(Clo)和拮抗剂育亨宾(Yoh)能分别模拟和阻断NA对GABA的作用。而β肾上腺素受体激动剂异丙肾上腺素(Iso),不能模拟NA对IGABA的抑制效应。百日咳毒素(IAP)敏感的G蛋白参与了NA对SGN IGABA抑制性调控。NA对SGN IGABA的抑制作用是由蛋白激酶A(PKA)相关的胞内信号转导机制介导的,蛋白激酶A抑制剂H-89能模拟NA对GABA的作用,在加入cAMP和蛋白激酶A激动剂时NA对IGABA的作用消失,但是在加入蛋白激酶C的激动剂PMA和抑制剂白屈菜赤碱(Che)时的,NA仍可抑制SGN IGABA。
结论
1培养新生大鼠SGN细胞的方法可获得良好状态的SGN细胞,SGN存活细胞的数量和周期可以满足体外穿孔膜片钳电生理实验的需要。
2穿孔膜片钳电生理结果表明NA对SGN细胞GABA电流的抑制作用是由α2肾上腺素受体介导的,α2肾上腺素受体激活后可通过抑制腺苷酸环化酶减少胞内cAMP含量,降低PKA活性,进而导致GABA对SGN的抑制作用减弱。表明源于交感系统的NA可通过抑制GABA反应来调控SGN的听觉信息传递。
Aim:
Spiral ganglion neurons (SGNs) in the cochlea receiveγ-aminobutyric acid (GABA)-ergic modulation through the lateral olivocochlear system from the superior olivary complex, and noradrenaline (NA)-ergic innervation from the superior cervical ganglion. But the modulatory effects of NA on GABA-activated responses in the SGNs remain unknown. In the present study, the modulatory effects of NA on the GABA responses were investigated in the isolated cultured SGNs of rat.
Methods:
The culture of SGN was carried out with postnatal day 0～5 SD rats. The process of cellular growth and differentiation of SGN were observed by fluorescent inverted/phase contrast microscope. Immunocytochemical identification was performed on the cultured SGN of SD rats by methods of fluorescence and the antibody of neuron-specific nuclear protein (NeuN). The effect of NA on GABA responses in the SGN was studied by using nystatin perforated patch recording configuration under voltage-clamp conditions. Results:
The trypsin dissociated and cultured SGN of SD rats could survive well and had a normal phenotypic differentiation in vitro. The stable neuronal plasticity of SGN existed in the postnatal SD rats under the present experimental conditions. NA reversibly depressed GABA responses in a concentration-dependent manner and neither changed the reversal potential of the GABA response nor affected the apparent affinity of GABA to its receptor.α2-adrenoceptor agonist and antagonist, clonidine and yohimbine mimicked and blocked the NA action on GABA response, respectively. N-[2(methylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride (H-89), a protein kinase A inhibitor, mimicked the effect of NA on GABA response. NA failed to affect the GABA response in the presence of both cyclic adenosine 5’-monophosphoric acid (cAMP) and protein kinase A modulators. However, NA still depressed the GABA response even in the presence of both phorbol-12-myristate-13-acetate (PMA), a protein kinase C activator and chelerythrine, a protein kinase C inhibitor.
Conclusion:
The cell amount and surviving period of cultured SGN were able to meet the requirements of cytological experiments. NA suppresses GABA response viaα2-adrenoceptor which reduces intracellular cAMP formation through the inhibition of adenyl cyclase. Therefore, NA input to the SGNs may modulate the auditory transmission by affecting the GABA responses.
引文
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