小鼠耳蜗螺旋神经节神经元GABA_A、nACh和NMDA受体表达变化和老年性耳聋机制的研究
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摘要
老年性耳聋(Presbycusis)是影响65岁以上人群的三大老年慢性疾病之一,目前超过半数以上的65岁以上老年人患有老年性听力障碍,而且有逐年上升趋势,越来越多的影响老年人生活的质量,我国现在老年性耳聋人数已超5000万人,我国已经步入老龄化社会,老年人口数量的增加必然带来老年疾患数量的增加。所有耳聋患者当中,有50%的人患有老年性耳聋。老年性耳聋以高频听力的敏感性降低,对言语分辨能力下降,背景噪声下听力障碍为特征,是基因遗传和环境因素相互做用引起的老年性退化性疾病,目前还未有有效生物医学手段来预防和治疗老年性耳聋。
老年性听功能障碍是中枢听觉系统和外周听觉系统共同退化的结果,中枢神经系统功能下降通常是由神经元功能退化引起,在耳蜗中,螺旋神经节神经元(SGN)是听觉传导通路的第一级神经元,是耳蜗毛细胞和听觉中枢之间的重要枢纽,因此螺旋神经节神经元发生年龄相关性退化是老年性耳聋外周神经系统发生发展的主要原因。感音神经性老年性聋是以耳蜗毛细胞及螺旋神经节神经元渐行性退化为特征,但不伴有血管纹和其他耳蜗附属器的明显改变的以高频听力损害为主的耳聋,是老年性耳聋中最常见的一种类型。谷氨酸(Glutamate)是听觉传入神经系统重要的兴奋性神经递质,在耳蜗内介导神经细胞的兴奋传递,维持听觉系统的正常生理功能,NMDA受体是谷氨酸离子型受体之一,当内毛细胞接收声信号刺激兴奋后释放出神经递质到突触,并与突触后膜上的NMDA受体结合,产生产生兴奋性突触后电位(EPSP)将声信号传入听中枢。但是当谷氨酸释放过量,过度激活NMDA受体的时候会产生神经细胞兴奋毒性作用,导致细胞死亡。γ-氨基丁酸(Gamma-aminobutyric acid,GABA)和N型乙酰胆碱(Nicotinic acetylcholine,nACh)是听觉传出神经系统的抑制性神经递质,保护耳蜗受外界强声刺激损伤,GABAA受体和nACh受体是听觉系统中重要的保护性受体。抑制性神经递质和兴奋性神经递质之间的平衡是维持听觉系统正常生理功能的关键。因此,为了更好的了解老年性耳聋在听觉外周神经系统耳蜗内的发生机制,本实验采用与人类听觉系统形态学和生理学上相似的CBA/CaJ小鼠,检测并探讨老年性耳聋听力生理学特点,并运用半定量RT-PCR和免疫组织化学技术检测其耳蜗螺旋神经节神经元细胞GABAA受体,nACh受体和NMDA受体的mRNA和蛋白质在老年性耳聋中的表达情况,观察老年性耳聋小鼠的耳蜗形态学的改变并讨论其意义。
方法：CBA/CaJ小鼠分为两组：成年组(2-6months n=22)和老年组(28-33months n=22)首先进行听觉脑干诱发电位(ABR)和畸变产物耳声发射(DPOAE)检测确定听力,然后解剖小鼠耳蜗,取一只耳蜗蜗轴提取总RNA,逆转录成cDNA,并用另一只耳蜗制备耳蜗冰冻切片,采用半定量RT-PCR和免疫组织化学检测成年组和老年组CBA小鼠耳蜗顶回,中间回,底回中的螺旋神经节神经元GABAA受体、nACh受体和NMDA受体亚单位的mRNA和蛋白质表达情况,并观察老年性耳蜗形态学上的改变。
实验结果：
(1)小鼠耳蜗螺旋神经节神经元有GABAARal, nAChRβ2and NMDARNR1表达。
(2) GABAA受体α1和nACh受体β2mRNA和蛋白质在老年性耳聋的小鼠SGN中表达下降,相反的,NMDA受体NR1mRNA和蛋白质在老年性聋的小鼠SGN中表达上升。
(3)老年小鼠较年轻大鼠的ARB3-48kHz的阈值均上升50dB以上。
(4)老年小鼠DPOAE各频率阈值增高,12,16kHz幅值减弱,其他频率反应未引出。
(5)老年小鼠耳蜗顶回,中间回和底回的螺旋神经节神经元密度均下降。其中底回螺旋神经元神经节密度下降程度最明显。
(6)老年性耳聋小鼠耳蜗SGN密度与ABR12,16kHz wave I振幅(Amplitude)存在线性正向相关关系,与ABR wave I潜伏期(Latency)存在线性负向相关关系。
结论：老年小鼠耳蜗螺旋节神经元上GABAA受体αl, nACh受体β2的下调和NMDA受体NR1表达上调是耳蜗SGN功能退化的基础,这些受体的表达变化导致耳蜗内突触传递功能的变化,受体间的相互作用和调节与老年性耳聋发生发展有密切的关系。老年CBA小鼠ABR和DPOAE各个频率阂值均有明显的升高,表明听觉传导通路第一级神经元SGNs以及上行各级神经元均有功能性的退化,外毛细胞数量减少和功能失调,SGN和听毛细胞的死亡和功能退化是老年性耳聋在外周听觉系统发生的主要原因。
Age-related hearing loss (ARHL)-Presbycusis is one of the top three most common chronic health conditions affecting individuals aged65years and older. Applying a conservative estimate of the prevalence rate of ARHL (50%) among the population65years and older in China. There are approximately50million senior citizens in China with significant hearing loss at present, and this number will be double in next20years. There are currently no biomedical treatments to prevent or reverse this condition. Age-related hearing loss is a disorder caused by mixed pathology include both genetic and environmental factors. Schuknecht classified presbycusis into four subtypes:(1) sensory (loss of hair cell), neural (loss of spiral ganglion neurons, SGNs), metabolic (atrophy of the stria vascularis) and mechanical (thickening and stiffening of the basilar membrane)."Sensorineural" presbycusis refers to the high-frequency-hearing impairment resulting from loss of hair cells and degeneration of SGNs without major changes in the function of the stra vascularis and other accessory structures of the inner ear which is a major contributor to age-related hearing loss. Neuron degeneration during age significantly contributes to functional decline of the central nervous system. In cochlea, SGNs connect the hair cells with central auditory system, it is the first neurons in auditory pathway. Thus, to study the etiologies of SGNs degeneration during aging paves a way to prevent or slow down the progression of age-related hearing loss as well as other types of hearing impairment. The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel ubiquitously distributed throughout the brain; it is fundamental for excitatory neurotransmission and normal central nervous system functions. NMDA receptors express at the same hair cell/afferent nerve synapse of a single spiral ganglion cell play a crucial complex role in normal physiological conditions for neurotransmission as well as for synaptic plasticity. NMDAR are important for neural communication, memory functions, learning processes, and mental performance and NMDARs are also involved in excitotoxicity in auditory system.Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system. The GAB AA receptor (GABAAR) is one of the most important inhibitory receptors, It plays a critical role in regulating neuronal excitability and information processing in the neuron system. The majority of GABAARs are widely expressed in the auditory system and it is a very important protective receptor in auditory efferent system.Acetylcholine (ACh) is the main transmitter released by the medial olivocochlear efferent fibers nAChR mainly located at the synapse between efferent fibers and outer hair cells (OHC).It is now believed that the hair cell cholinergic receptor that mediates synaptic transmission between efferent olivocohlear fibers and hair cells of the cochlea, is formed by both a9and a10subunits. The activation of the hair cell nAChR leads to an increase in intracellular Ca+-activated K+(SK2) channels thus leading to hyperpolarization of hair cells and reduction of electromotility. The auditory system of CBA/CaJ strain is very similar to human physiologically and morphologically during aging, therefore it is a good model for studying sensorineural presbycusis with high-frequency hearing loss accompanied by hair cells loss, neuronal degeneration. A better understanding of the cochlear mechanisms underlying peripheral presbycusis will help lead to future treatments. Objectives of the present study were to investigate gamma-amino butyric acid A (GABAA) receptor subunit al, nicotinic acetylcholine (nACh) receptor subunit (32, and N-methyl-D-aspartate (NMDA) receptor subunit NR1mRNA and protein expression changes in spiral ganglion neurons (SGN) of the young adult and old mouse cochlea, utilizing quantitative immunohistochemistry and RT-PCR techniques and observe the hair cells and SGNs in cochlear mophyological change with age.
Methods:ABR RECORDING PROCEDURES Young adult (Male3, Female3), old age (Male3, Female3) were anesthetized with a mixture of ketamine/xylazine (120and10mg/kg body weight, intraperitoneal injection) prior to all experimental sessions. All recording sessions were completed in a sound proof acoustic chamber (LAC lined with Sonex) with body temperature maintained with a heating pad. ABRs were measured using Biosig (TDT Gainesville, FL) data-acquisition system in response5ms tone pips (0.5-m rise fall times) with cos2onset envelop presented at rate of29/sec. Threshold was defined as the lowest intensity which elicited a clearly replicable response. IMMUNOCYCHEMISTRY Sacrificed the mice and dissected the cochlea. Cochlea were fixed in4%paraformaldehyde in PBS overnight at4℃and decalcified in10%EDTA in PBS for three days at4℃. After using cryoprotectant for cryoprotection overnight at4℃,the cochlea were embedded into degassed OCT overnight at4℃, oriented into the cryomold with OCT, degassed for1hour, then fast frozen. Cryosectioning was performed at5μm/section. The cochlea slides were stained with DAB using antibody GABAARa1,NMDARNR1or nAChRβ2. qRT-PCR10ng of total RNA was reverse transcribed and complementary DNA was amplified,and quantitative PCR was performed using Enhanced Avian HS RT-PCR100Kit.
Results:(1) GABAARa1, nAChRβ2and NMDARNR1were detected in spiral ganglion neurons of CBA/CaJ mouse cochlea.(2) mRNA and protein expression of GABAARal and nAChRβ2decreased with age in spiral ganglion neurons of mouse cochlea. mRNA and protein expression of NMDARNR1increased with age in spiral ganglion neurons of mouse cochlea.(3) ABR thresholds shift over50dB from3-48kHz in old mice compared to young adult mice.(4)DPOAE thresholds shift over40of6,12,16,30,44kHz in old mice compared to young adult mice.12and16kHz of DPOAE amplitude decreased and the other frequency response were absent in the old mice.(5) SGN density decreased with age in basal, middle and apical turns, and SGN density of the basal turn decreased the most.(6) Correlations were observed between SGN density and ABR wave I Amplitude/ABR wave I Latency. There is a possive correlation between SGN density and ABR wave I Amplitude and a negative correlation between SGN density and ABR wave I Latency.
Summary and Conclusions:Age-related changes of GABAARal, nAChR(32and NMDARNR1expression in CBA mouse SGNs were observed, which may be related to functional changes in cochlear synaptic transmission as a function of age. ABR thresholds and DPOAE shift over50dB from all the prequancy in old mice indicated that auditory function delince in all the level of auditory pathway, SGNs density and OHC significantly declined with age, all these are associated with age-related peripheral auditory system impairment and fianlly lead to age-related hearing loss. This finding leads to more insights into the function of these three cochlea receptors concerning their regulation in the aging mammalian auditory system, paving the way for novel biomedical interventions to prevent or slow down the progression of age-related hearing loss as well as other types of hearing impairment.
老年性听功能障碍是中枢听觉系统和外周听觉系统共同退化的结果,中枢神经系统功能下降通常是由神经元功能退化引起,在耳蜗中,螺旋神经节神经元(SGN)是听觉传导通路的第一级神经元,是耳蜗毛细胞和听觉中枢之间的重要枢纽,因此螺旋神经节神经元发生年龄相关性退化是老年性耳聋外周神经系统发生发展的主要原因。感音神经性老年性聋是以耳蜗毛细胞及螺旋神经节神经元渐行性退化为特征,但不伴有血管纹和其他耳蜗附属器的明显改变的以高频听力损害为主的耳聋,是老年性耳聋中最常见的一种类型。谷氨酸(Glutamate)是听觉传入神经系统重要的兴奋性神经递质,在耳蜗内介导神经细胞的兴奋传递,维持听觉系统的正常生理功能,NMDA受体是谷氨酸离子型受体之一,当内毛细胞接收声信号刺激兴奋后释放出神经递质到突触,并与突触后膜上的NMDA受体结合,产生产生兴奋性突触后电位(EPSP)将声信号传入听中枢。但是当谷氨酸释放过量,过度激活NMDA受体的时候会产生神经细胞兴奋毒性作用,导致细胞死亡。γ-氨基丁酸(Gamma-aminobutyric acid,GABA)和N型乙酰胆碱(Nicotinic acetylcholine,nACh)是听觉传出神经系统的抑制性神经递质,保护耳蜗受外界强声刺激损伤,GABAA受体和nACh受体是听觉系统中重要的保护性受体。抑制性神经递质和兴奋性神经递质之间的平衡是维持听觉系统正常生理功能的关键。因此,为了更好的了解老年性耳聋在听觉外周神经系统耳蜗内的发生机制,本实验采用与人类听觉系统形态学和生理学上相似的CBA/CaJ小鼠,检测并探讨老年性耳聋听力生理学特点,并运用半定量RT-PCR和免疫组织化学技术检测其耳蜗螺旋神经节神经元细胞GABAA受体,nACh受体和NMDA受体的mRNA和蛋白质在老年性耳聋中的表达情况,观察老年性耳聋小鼠的耳蜗形态学的改变并讨论其意义。
方法：CBA/CaJ小鼠分为两组：成年组(2-6months n=22)和老年组(28-33months n=22)首先进行听觉脑干诱发电位(ABR)和畸变产物耳声发射(DPOAE)检测确定听力,然后解剖小鼠耳蜗,取一只耳蜗蜗轴提取总RNA,逆转录成cDNA,并用另一只耳蜗制备耳蜗冰冻切片,采用半定量RT-PCR和免疫组织化学检测成年组和老年组CBA小鼠耳蜗顶回,中间回,底回中的螺旋神经节神经元GABAA受体、nACh受体和NMDA受体亚单位的mRNA和蛋白质表达情况,并观察老年性耳蜗形态学上的改变。
实验结果：
(1)小鼠耳蜗螺旋神经节神经元有GABAARal, nAChRβ2and NMDARNR1表达。
(2) GABAA受体α1和nACh受体β2mRNA和蛋白质在老年性耳聋的小鼠SGN中表达下降,相反的,NMDA受体NR1mRNA和蛋白质在老年性聋的小鼠SGN中表达上升。
(3)老年小鼠较年轻大鼠的ARB3-48kHz的阈值均上升50dB以上。
(4)老年小鼠DPOAE各频率阈值增高,12,16kHz幅值减弱,其他频率反应未引出。
(5)老年小鼠耳蜗顶回,中间回和底回的螺旋神经节神经元密度均下降。其中底回螺旋神经元神经节密度下降程度最明显。
(6)老年性耳聋小鼠耳蜗SGN密度与ABR12,16kHz wave I振幅(Amplitude)存在线性正向相关关系,与ABR wave I潜伏期(Latency)存在线性负向相关关系。
结论：老年小鼠耳蜗螺旋节神经元上GABAA受体αl, nACh受体β2的下调和NMDA受体NR1表达上调是耳蜗SGN功能退化的基础,这些受体的表达变化导致耳蜗内突触传递功能的变化,受体间的相互作用和调节与老年性耳聋发生发展有密切的关系。老年CBA小鼠ABR和DPOAE各个频率阂值均有明显的升高,表明听觉传导通路第一级神经元SGNs以及上行各级神经元均有功能性的退化,外毛细胞数量减少和功能失调,SGN和听毛细胞的死亡和功能退化是老年性耳聋在外周听觉系统发生的主要原因。
Age-related hearing loss (ARHL)-Presbycusis is one of the top three most common chronic health conditions affecting individuals aged65years and older. Applying a conservative estimate of the prevalence rate of ARHL (50%) among the population65years and older in China. There are approximately50million senior citizens in China with significant hearing loss at present, and this number will be double in next20years. There are currently no biomedical treatments to prevent or reverse this condition. Age-related hearing loss is a disorder caused by mixed pathology include both genetic and environmental factors. Schuknecht classified presbycusis into four subtypes:(1) sensory (loss of hair cell), neural (loss of spiral ganglion neurons, SGNs), metabolic (atrophy of the stria vascularis) and mechanical (thickening and stiffening of the basilar membrane)."Sensorineural" presbycusis refers to the high-frequency-hearing impairment resulting from loss of hair cells and degeneration of SGNs without major changes in the function of the stra vascularis and other accessory structures of the inner ear which is a major contributor to age-related hearing loss. Neuron degeneration during age significantly contributes to functional decline of the central nervous system. In cochlea, SGNs connect the hair cells with central auditory system, it is the first neurons in auditory pathway. Thus, to study the etiologies of SGNs degeneration during aging paves a way to prevent or slow down the progression of age-related hearing loss as well as other types of hearing impairment. The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel ubiquitously distributed throughout the brain; it is fundamental for excitatory neurotransmission and normal central nervous system functions. NMDA receptors express at the same hair cell/afferent nerve synapse of a single spiral ganglion cell play a crucial complex role in normal physiological conditions for neurotransmission as well as for synaptic plasticity. NMDAR are important for neural communication, memory functions, learning processes, and mental performance and NMDARs are also involved in excitotoxicity in auditory system.Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system. The GAB AA receptor (GABAAR) is one of the most important inhibitory receptors, It plays a critical role in regulating neuronal excitability and information processing in the neuron system. The majority of GABAARs are widely expressed in the auditory system and it is a very important protective receptor in auditory efferent system.Acetylcholine (ACh) is the main transmitter released by the medial olivocochlear efferent fibers nAChR mainly located at the synapse between efferent fibers and outer hair cells (OHC).It is now believed that the hair cell cholinergic receptor that mediates synaptic transmission between efferent olivocohlear fibers and hair cells of the cochlea, is formed by both a9and a10subunits. The activation of the hair cell nAChR leads to an increase in intracellular Ca+-activated K+(SK2) channels thus leading to hyperpolarization of hair cells and reduction of electromotility. The auditory system of CBA/CaJ strain is very similar to human physiologically and morphologically during aging, therefore it is a good model for studying sensorineural presbycusis with high-frequency hearing loss accompanied by hair cells loss, neuronal degeneration. A better understanding of the cochlear mechanisms underlying peripheral presbycusis will help lead to future treatments. Objectives of the present study were to investigate gamma-amino butyric acid A (GABAA) receptor subunit al, nicotinic acetylcholine (nACh) receptor subunit (32, and N-methyl-D-aspartate (NMDA) receptor subunit NR1mRNA and protein expression changes in spiral ganglion neurons (SGN) of the young adult and old mouse cochlea, utilizing quantitative immunohistochemistry and RT-PCR techniques and observe the hair cells and SGNs in cochlear mophyological change with age.
Methods:ABR RECORDING PROCEDURES Young adult (Male3, Female3), old age (Male3, Female3) were anesthetized with a mixture of ketamine/xylazine (120and10mg/kg body weight, intraperitoneal injection) prior to all experimental sessions. All recording sessions were completed in a sound proof acoustic chamber (LAC lined with Sonex) with body temperature maintained with a heating pad. ABRs were measured using Biosig (TDT Gainesville, FL) data-acquisition system in response5ms tone pips (0.5-m rise fall times) with cos2onset envelop presented at rate of29/sec. Threshold was defined as the lowest intensity which elicited a clearly replicable response. IMMUNOCYCHEMISTRY Sacrificed the mice and dissected the cochlea. Cochlea were fixed in4%paraformaldehyde in PBS overnight at4℃and decalcified in10%EDTA in PBS for three days at4℃. After using cryoprotectant for cryoprotection overnight at4℃,the cochlea were embedded into degassed OCT overnight at4℃, oriented into the cryomold with OCT, degassed for1hour, then fast frozen. Cryosectioning was performed at5μm/section. The cochlea slides were stained with DAB using antibody GABAARa1,NMDARNR1or nAChRβ2. qRT-PCR10ng of total RNA was reverse transcribed and complementary DNA was amplified,and quantitative PCR was performed using Enhanced Avian HS RT-PCR100Kit.
Results:(1) GABAARa1, nAChRβ2and NMDARNR1were detected in spiral ganglion neurons of CBA/CaJ mouse cochlea.(2) mRNA and protein expression of GABAARal and nAChRβ2decreased with age in spiral ganglion neurons of mouse cochlea. mRNA and protein expression of NMDARNR1increased with age in spiral ganglion neurons of mouse cochlea.(3) ABR thresholds shift over50dB from3-48kHz in old mice compared to young adult mice.(4)DPOAE thresholds shift over40of6,12,16,30,44kHz in old mice compared to young adult mice.12and16kHz of DPOAE amplitude decreased and the other frequency response were absent in the old mice.(5) SGN density decreased with age in basal, middle and apical turns, and SGN density of the basal turn decreased the most.(6) Correlations were observed between SGN density and ABR wave I Amplitude/ABR wave I Latency. There is a possive correlation between SGN density and ABR wave I Amplitude and a negative correlation between SGN density and ABR wave I Latency.
Summary and Conclusions:Age-related changes of GABAARal, nAChR(32and NMDARNR1expression in CBA mouse SGNs were observed, which may be related to functional changes in cochlear synaptic transmission as a function of age. ABR thresholds and DPOAE shift over50dB from all the prequancy in old mice indicated that auditory function delince in all the level of auditory pathway, SGNs density and OHC significantly declined with age, all these are associated with age-related peripheral auditory system impairment and fianlly lead to age-related hearing loss. This finding leads to more insights into the function of these three cochlea receptors concerning their regulation in the aging mammalian auditory system, paving the way for novel biomedical interventions to prevent or slow down the progression of age-related hearing loss as well as other types of hearing impairment.
引文
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