SRC-1在小鼠脑内表达的性别差异及其对性别依赖的海马突触可塑性作用的初步研究
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摘要
哺乳动物脑结构和功能存在性别差异。比如,雄性下丘脑与生殖有关的性别二态性核团的体积大于雌性、雄鸟高声区的体积大于雌性、男性的抽象思维较强而女性的形象思维较强。海马作为与学习记忆、认知情绪、应激等关系密切的重要脑区,依赖于海马的结构和生理功能也存在性别差异,而且脑老化导致的神经退行性疾病阿尔茨海默氏病的发病率在女性高于男性,而老年男性患帕金森病的比例高于女性。造成这些性别差异的分子机制尚不清楚。已经知道雄激素、雌激素等类固醇激素通过其核受体对海马的结构和包括突触发生在内的突触可塑性等功能具有重要的调节作用,而这些激素及其受体是如何调节包括海马在内的脑结构与功能的性别差异还不明确。
类固醇激素及其受体对靶基因的调节需要辅助活化因子的参与。类固醇受体辅助活化因子-1 (steroid receptor coactivator-1, SRC-1)是脑内分布最广泛的类固醇受体辅助活化因子,参与了雌激素受体、雄激素受体等多种类固醇受体对把基因转录的调节。敲除SRC-1基因导致小脑浦肯野细胞发育延迟、依赖小脑的运动能力障碍、依赖海马的水迷宫学习记忆行为障碍,而向下丘脑注射SRC-1反义核苷酸显著改变下丘脑的神经可塑性以及生殖行为,表明SRC-1对脑结构与功能的重要性。但SRC-1在脑内的表达是否具有性别差异、其表达的性别差异与脑结构和功能的性别差异有何关系尚未见文献报道。为了回答上述问题,我们运用免疫组化技术检测了SRC-1在成年雌性和雄性小鼠脑内的分布情况及性别差异,为阐明性别依赖的脑的结构、功能及行为的机制奠定基础。
由于海马是类固醇激素作用于中枢神经系统的重要功能区域,基于海马的学习记忆、认知情绪、应激等功能具有性别差异,那么SRC-1在海马的发育表达是否具有性别差异?如果有,此差异是否与海马结构和功能的性别差异有关?为回答此问题我们采用免疫组化和Westen Blot等技术检测了SRC-1和突触蛋白Synaptophysin(SYN)、AMPA受体亚型谷氨酸受体-1(GluR-1)、突触后致密物蛋白-95(Postsynaptic densityprotein-95, PSD-95)在出生后P0、P7、P14、P30、P60时海马的发育表达变化及性别差异并采用统计学方法分别进行了相关性分析,以明确SRC-1在海马发育表达的性别差异在介导海马突触发生的性别差异中的作用。
既往的研究表明老化伴随有循环性激素水平的下降,从而导致依赖于海马的结构功能的改变进而引发相关神经退行性疾病如老年痴呆和帕金森病,其发病和病理特征都有性别依赖性,激素替代治疗在一定程度上可以改善并缓解神经功能障碍。SRC-1作为重要的类固醇激素调节海马突触可塑性的辅助活化因子,在介导老化过程中性别依赖的海马结构与功能中起何作用?为了阐明以上问题,我们通过经典的卵巢切除和睾丸切除模型模拟老化后循环激素水平降低,采用免疫组化和Westen Blot技术检测了在性腺切除后1周、2周、4周时海马SRC-1和突触蛋白SYN、GluR-1、PSD-95的表达变化及性别差异并进行了有关的相关性分析,以初步探讨SRC-1可能介导老化引起的海马功能障碍的性别差异的机制,为进一步认知SRC-1在调节海马结构功能的性别差异提供新的线索和依据。
主要结果：
1、SRC-1免疫阳性产物广泛表达于成年雌性和雄性小鼠脑内,嗅球、大脑皮质、海马、下丘脑、小脑和脑干的部分核团有高水平表达；中等水平的表达出现在丘脑和脑干的大部分核团；较低水平或阴性表达见于纹状体等部位。
2、SRC-1主要表达在大部分脑区的细胞核中,但有极少量免疫阳性产物出现在与运动调节有关区域的核外,如脑干的三叉神经运动根的纤维样结构。
3、雄性小鼠大部分脑区SRC-1表达均显著高于动情间期低雌激素水平的雌性,只有少数区域低于雌性但并无统计学意义。
4、SRC-1在雌性小鼠海马内的表达在PO时极低,随发育显著升高并于P14时达到峰值,随后到P30显著降低,P60时维持较高水平；雄性小鼠海马SRC-1的表达从出生到成年表达持续升高,在P30达到峰值,P60略微降低但仍维持较高水平。
5、突触蛋白SYN、GluR-1及PSD-95在雌性和雄性小鼠海马的发育表达模式分别一致。SYN在PO时表达最低,随发育逐渐升高并在P30达到峰值,随后保持较高水平；GluR-1出生时表达很低,随发育逐渐升高,P30到达表达的最高峰,P60有所下降；PSD-95的发育表达模式为增龄性持续性升高,P60时达到峰值。
6、SRC-1在雌性和雄性小鼠海马发育表达模式与SYN、GluR-1及PSD-95的发育表达模式有高度一致的线性相关关系,其中雌性SRC-1与GluR-1表达模式最相关,雄性SRC-1与SYN的表达模式最相关。
7、性腺切除后雌性和雄性海马内SRC-1的表达均发生变化。其中雌性在卵巢切除后两周时海马SRC-1的表达显著降低,第四周时即恢复至正常水平；雄性睾丸切除后一周海马SRC-1表达就开始显著降低并持续降低。
8、性腺切除后海马内SYN的表达变化无差异,而GluR-1及PSD-95均发生变化。其中雌性在卵巢切除后两周时海马GluR-1的表达显著降低,第四周时恢复到正常水平,雄性睾丸切除后海马内GluR-1的表达持续降低；雌性海马PSD-95的表达只在卵巢切除四周时才有显著性降低,雄性睾丸切除后海马PSD-95的变化持续降低。
9、卵巢切除后雌性小鼠海马内SRC-1表达的变化与GluR-1存在高度一致的线性相关关系；睾丸切除后雄性小鼠海马内SRC-1表达的变化与GluR-1和PSD-95均存在高度一致的线性相关关系。
主要结论：
1、SRC-1在成年雌性和雄性小鼠脑内的广泛表达提示其在脑内参与了多种脑功能作用的调节；少量阳性产物出现在脑干的纤维样结构中提示SRC-1在此处有可能通过非基因型的信号途径介导类固醇激素对脑运动功能的调节。
2、SRC-1在成年小鼠脑内的表达具有性别差异,在大部分脑区内雄性的表达高于雌性,提示SRC-1脑内表达的性别差异可能与脑功能的性别差异和性别依赖的老化所致神经退行性疾病的发病和病理表现有关。
3、雌性和雄性小鼠海马SRC-1和突触蛋白SYN、GluR-1及PSD-95发育表达均具有性别差异且SRC-1的表达模式与SYN、GluR-1及PSD-95的表达模式高度相关,提示SRC-1可能在调节海马突触发生中具有重要作用,生后海马SRC-1表达的性别差异可能是突触发生具有性别差异的主要原因。
4、性腺切除对海马SRC-1和突触蛋白表达的影响具有性别差异,卵巢切除后海马SRC-1表达变化与GluR-1表达高度相关,其表达均短暂降低；睾丸切除后海马SRC-1表达变化与GluR-1和PSD-95表达均高度相关,其表达均持续降低。提示循环性激素对海马SRC-1表达的影响具有性别差异,这种差异可能进一步导致海马突触可塑性的性别差异性改变,并最终导致老化过程中依赖于海马的结构和功能的性别差异。
总之,本研究运用免疫组织化学技术、Western blot等技术方法,研究了SRC-1在成年雌性和雄性小鼠脑内的表达定位及性别差异,以及SRC-1在海马的发育表达模式与突触蛋白SYN、GluR-1、PSD-95的发育表达模式的性别差异及相关性,并通过性腺切除模型的建立观察循环性激素对海马SRC-1和突触蛋白表达的影响及性别差异,初步探讨了SRC-1在调节海马突触可塑性中的作用,为进一步深入研究基于海马的结构和功能存在性别差异的机制提供了可靠的线索和依据。
It is well-known that sex differences of structure and function exist between female and male mammalian brain. For example, males have lager volume of the sexually dimorphic nucleus associated with reproduction in hypothalaums than females, and men's abstract thinking is better but women's imagery thinking is better. Hippocampus is an important brain region which has been profoundly invovled in learning and memory, cognition, emotion and stress, sex-specific differences have also been noticed in these hippocampal-dependent structure and physiological function. For example, the size of male hippocampus is slight but significant larger than the females, and the incidence of Alzheimer's disease, a neurological degenerative disease induced by brain aging, is higher in the females than in the males. So far, the molecular mechanisms underlying these sex differences remain unclear. It is known that steroids, such as androgen and estrogens, can regulate hippocampal structure and synaptic plasticity through their nuclear receptors including androgen receptor (AR), estrogen receptor-αand-β(ERa; ERp), but how do these hormones and their receptors regulate sex difference in brain especially hippocampal structure and function is also unclear.
It's clear that the regulation of steroids and their receptors of target gene needs their cofactors including coactivators and corepressors. Steroid receptor coactivator-1(SRC-1) is the most widely distributed steroid receptor coactivator in the brain. It participate the regulation of several kinds of steroid receptors for gene transcription. Studies have shown that SRC-1 gene deficiency results in delayed development of cerebellar Purkinje cells, motor function disorder and significant longer escape latency in Morris maze test. Additionally, infusion SRC-1 antisense nucleotide into hypothalamus significantly changes neural plasticity and reproductive behavior. Previously we have demonstrated high levels of SRC-1 in the adult female rat brain, indicating its multiple function in mediating steroids action in the regulation of brain structure and function. But whether there is any sex difference in the distribution of SRC-1 in the female and male brain and, if so, how about its relationship with brain dimorphism remains to be elucidated.
Hippocampus is the most important functional brain region and deeply affected by circulating and/or local steroids. Some sex differences of the structure and function of hippocampus have been noticed by previous studies. Whether there is any sex difference of SRC-1 expression in the hippocampus during postnatal development and whether this difference is associated with the hippocampal synaptogenesis is not clear. Since sex hormones affect hippocampus in a sex-dependant manner, how about the effects of circulating sex hormones on hippocampal SRC-1 expression and what is the relationship between these effects and hippocampal synaptic plasticity is also unclear.
In order to address these questions, we first used immunohistochemistry to examine the distribution of SRC-1 in the brain of adult female and male mice. Then, we studied the ontogeny of hippocampal SRC-1 and some important synaptic proteins including synaptophysin (SYN), AMPA receptor subtype GluR-1 and postsynaptic density-95 (PSD-95) at different postnatal stages in the female and male mice and explored the correlation between the profile of SRC-1 and synaptic proteins in each sex. Finally, by using the classic steroids-deficiency gonadectomy model to mimic the decline of circular hormone level during aging we examined the expression of hippocampal SRC-1, SYN, GluR-1, PSD-95 at 1-,2- and 4-week after surgery of both sexes and evaluated the correlation of changes between SRC-1 and each synaptic protein.
Main results:
1. SRC-1 immunopositive materials were widely detected in the brain of adult female and male mice. High levels were detected in the olfactory bulb, cerebral cortex, hippocampus, hypothalamus, cerebellum and some nuclei of brainstem. Moderate levels were detected in the thalamus and most nuclei of brainstem, and no or lower levels of SRC-1 were also detected in some specific brain regions.
2. SRC-1 immunopositive materials were predominantly detected in the cell nucleus of mice brain, but in some limited regions associated with motion regulation, it seemed they were also detected in neuritis fiber-like structure of motor root of trigeminal nerve of the brainstem.
3. Male brain showed statistically significant higher levels of SRC-1 immunoreactivities when compared with that of the diestrus females, in very limited regions female brain showed higher levels of SRC-1 immunoreactivities than males but without statistically significance.
4. The expression of SRC-1 in the hippocampus of female was very low at PO.It significantly increased with development and reached the peak at P14, and significantly decreased at P30 and sustained a high level at P60. However, the developmental change of SRC-1 in hippocampus of male was increased from PO to P30, and reached the peak at P30 and then sustained a high level at P60.
5. As to the postnatal developmental profile of hippocampal SYN, GluR-1 and PSD-95, the results showed that females and males shared similar patterns. The levels of SYN and GluR-1 were the lowest at PO but gradually increased with development and reached the peak at P30 and then maintained a high level, levels of PSD-95 were also increased from PO but the peak expression was found at P60.
6. The developmental profile of SRC-1 in hippocampus of female and male mice showed high consistent linear correlation with that of SYN, GluR-1 and PSD-95, respectively, in each sex. The highest correlation was detected between SRC-1/GluR-1 in females and SRC-1/SYN in males.
7. Circulating sex hormones affected hippocampal SRC-1 in a sex-dependant manner, as demonstrated by gonadectomy. Hippocampal SRC-1 levels decreased significantly 2 weeks after ovariectomy but recovered to normal at 4 weeks in females, while in males it decreased right after orchiectomy. GluR-1 showed identical alterations to SRC-1 after gonadectomy,
8. Although hippocampal SYN was not affected by gonadectomy, significant changes of GluR-1 and PSD-95 after gonadectomy were noticed. GluR-1 showed identical changes as that of SRC-1 in both sexes, levels of PSD-95 in female only decreased significantly at 4weeks after ovariectomy but in the males it gradually decreased after orchiectomy.
9. The highest linear correlation was found between SRC-1 and GluR-1 in the female after ovariectomy; and this was found between SRC-1/GluR-1 and SRC-1/PSD-95 after orchiectomy.
Main conclusion:
1. SRC1-is widely distributed in the brain of both female and male mice, significant male-predominance was detected, indicating a multi-function role of SRC-1 in the regulation of various brain function and this sex-dependant distribution may contribute to the sex-difference of some steroid-related brain structure and function.
2. Different extent of sex differences in regarding of the postnatal developmental profiles of hippocampal SRC-1, SYN, GluR-1 and PSD-95 of female and male mice were noticed, correlation analysis showed that SRC-1 is highly related to that of the synaptic proteins, and these results strongly imply a potential role that SRC-1 play in the regulation of hippocampal synaptogenesis in a sex-specific manner.
3. Circulating sex hormones regulate hippocampal SRC-1 in a sex-dependant manner, as demonstrated by gonadectomy. Some synaptic proteins were also regulated by sex hormones as that of SRC-1. Furthermore, correlation analysis revealed that change of SRC-1 is highly with that of some of the synaptic proteins. All these strongly suggest that age-related decrease of SRC-1 may contribute the decreased synaptic plasticity in the hippocampus of female and male mice, in a sex-dependant manner.
In short, the results of our study demonstrate that SRC-1, which widespreads in the brain and expresses differently between females and males, is potentially involved in the regulation of a variety of brain function and mediate the sex difference of brain structure and function. Sex difference in the developmental expression of SRC-1 in hippocampus and being highly correlated with the developmental model of several synaptic proteins suggest the sex difference of SRC-1 may possibly mediate the sex difference of hippocampal synaptogenesis. Moreover, gonad hormones affect hippocampal SRC-1 in a sex-dependant manner, and this change is also highly related with that of these synaptic proteins,implying the sex difference of SRC-1 may further participate in the changes based on sex difference of hippocampal synaptic plasticity and finally effect sex difference of hippocampus-dependent structure and function during the process of aging. Therefore, this study provides some reliable clues for advanced understanding of the mechanisms in sex difference of structure and functions involved in the brain especially in the hippocampus.
类固醇激素及其受体对靶基因的调节需要辅助活化因子的参与。类固醇受体辅助活化因子-1 (steroid receptor coactivator-1, SRC-1)是脑内分布最广泛的类固醇受体辅助活化因子,参与了雌激素受体、雄激素受体等多种类固醇受体对把基因转录的调节。敲除SRC-1基因导致小脑浦肯野细胞发育延迟、依赖小脑的运动能力障碍、依赖海马的水迷宫学习记忆行为障碍,而向下丘脑注射SRC-1反义核苷酸显著改变下丘脑的神经可塑性以及生殖行为,表明SRC-1对脑结构与功能的重要性。但SRC-1在脑内的表达是否具有性别差异、其表达的性别差异与脑结构和功能的性别差异有何关系尚未见文献报道。为了回答上述问题,我们运用免疫组化技术检测了SRC-1在成年雌性和雄性小鼠脑内的分布情况及性别差异,为阐明性别依赖的脑的结构、功能及行为的机制奠定基础。
由于海马是类固醇激素作用于中枢神经系统的重要功能区域,基于海马的学习记忆、认知情绪、应激等功能具有性别差异,那么SRC-1在海马的发育表达是否具有性别差异?如果有,此差异是否与海马结构和功能的性别差异有关?为回答此问题我们采用免疫组化和Westen Blot等技术检测了SRC-1和突触蛋白Synaptophysin(SYN)、AMPA受体亚型谷氨酸受体-1(GluR-1)、突触后致密物蛋白-95(Postsynaptic densityprotein-95, PSD-95)在出生后P0、P7、P14、P30、P60时海马的发育表达变化及性别差异并采用统计学方法分别进行了相关性分析,以明确SRC-1在海马发育表达的性别差异在介导海马突触发生的性别差异中的作用。
既往的研究表明老化伴随有循环性激素水平的下降,从而导致依赖于海马的结构功能的改变进而引发相关神经退行性疾病如老年痴呆和帕金森病,其发病和病理特征都有性别依赖性,激素替代治疗在一定程度上可以改善并缓解神经功能障碍。SRC-1作为重要的类固醇激素调节海马突触可塑性的辅助活化因子,在介导老化过程中性别依赖的海马结构与功能中起何作用?为了阐明以上问题,我们通过经典的卵巢切除和睾丸切除模型模拟老化后循环激素水平降低,采用免疫组化和Westen Blot技术检测了在性腺切除后1周、2周、4周时海马SRC-1和突触蛋白SYN、GluR-1、PSD-95的表达变化及性别差异并进行了有关的相关性分析,以初步探讨SRC-1可能介导老化引起的海马功能障碍的性别差异的机制,为进一步认知SRC-1在调节海马结构功能的性别差异提供新的线索和依据。
主要结果：
1、SRC-1免疫阳性产物广泛表达于成年雌性和雄性小鼠脑内,嗅球、大脑皮质、海马、下丘脑、小脑和脑干的部分核团有高水平表达；中等水平的表达出现在丘脑和脑干的大部分核团；较低水平或阴性表达见于纹状体等部位。
2、SRC-1主要表达在大部分脑区的细胞核中,但有极少量免疫阳性产物出现在与运动调节有关区域的核外,如脑干的三叉神经运动根的纤维样结构。
3、雄性小鼠大部分脑区SRC-1表达均显著高于动情间期低雌激素水平的雌性,只有少数区域低于雌性但并无统计学意义。
4、SRC-1在雌性小鼠海马内的表达在PO时极低,随发育显著升高并于P14时达到峰值,随后到P30显著降低,P60时维持较高水平；雄性小鼠海马SRC-1的表达从出生到成年表达持续升高,在P30达到峰值,P60略微降低但仍维持较高水平。
5、突触蛋白SYN、GluR-1及PSD-95在雌性和雄性小鼠海马的发育表达模式分别一致。SYN在PO时表达最低,随发育逐渐升高并在P30达到峰值,随后保持较高水平；GluR-1出生时表达很低,随发育逐渐升高,P30到达表达的最高峰,P60有所下降；PSD-95的发育表达模式为增龄性持续性升高,P60时达到峰值。
6、SRC-1在雌性和雄性小鼠海马发育表达模式与SYN、GluR-1及PSD-95的发育表达模式有高度一致的线性相关关系,其中雌性SRC-1与GluR-1表达模式最相关,雄性SRC-1与SYN的表达模式最相关。
7、性腺切除后雌性和雄性海马内SRC-1的表达均发生变化。其中雌性在卵巢切除后两周时海马SRC-1的表达显著降低,第四周时即恢复至正常水平；雄性睾丸切除后一周海马SRC-1表达就开始显著降低并持续降低。
8、性腺切除后海马内SYN的表达变化无差异,而GluR-1及PSD-95均发生变化。其中雌性在卵巢切除后两周时海马GluR-1的表达显著降低,第四周时恢复到正常水平,雄性睾丸切除后海马内GluR-1的表达持续降低；雌性海马PSD-95的表达只在卵巢切除四周时才有显著性降低,雄性睾丸切除后海马PSD-95的变化持续降低。
9、卵巢切除后雌性小鼠海马内SRC-1表达的变化与GluR-1存在高度一致的线性相关关系；睾丸切除后雄性小鼠海马内SRC-1表达的变化与GluR-1和PSD-95均存在高度一致的线性相关关系。
主要结论：
1、SRC-1在成年雌性和雄性小鼠脑内的广泛表达提示其在脑内参与了多种脑功能作用的调节；少量阳性产物出现在脑干的纤维样结构中提示SRC-1在此处有可能通过非基因型的信号途径介导类固醇激素对脑运动功能的调节。
2、SRC-1在成年小鼠脑内的表达具有性别差异,在大部分脑区内雄性的表达高于雌性,提示SRC-1脑内表达的性别差异可能与脑功能的性别差异和性别依赖的老化所致神经退行性疾病的发病和病理表现有关。
3、雌性和雄性小鼠海马SRC-1和突触蛋白SYN、GluR-1及PSD-95发育表达均具有性别差异且SRC-1的表达模式与SYN、GluR-1及PSD-95的表达模式高度相关,提示SRC-1可能在调节海马突触发生中具有重要作用,生后海马SRC-1表达的性别差异可能是突触发生具有性别差异的主要原因。
4、性腺切除对海马SRC-1和突触蛋白表达的影响具有性别差异,卵巢切除后海马SRC-1表达变化与GluR-1表达高度相关,其表达均短暂降低；睾丸切除后海马SRC-1表达变化与GluR-1和PSD-95表达均高度相关,其表达均持续降低。提示循环性激素对海马SRC-1表达的影响具有性别差异,这种差异可能进一步导致海马突触可塑性的性别差异性改变,并最终导致老化过程中依赖于海马的结构和功能的性别差异。
总之,本研究运用免疫组织化学技术、Western blot等技术方法,研究了SRC-1在成年雌性和雄性小鼠脑内的表达定位及性别差异,以及SRC-1在海马的发育表达模式与突触蛋白SYN、GluR-1、PSD-95的发育表达模式的性别差异及相关性,并通过性腺切除模型的建立观察循环性激素对海马SRC-1和突触蛋白表达的影响及性别差异,初步探讨了SRC-1在调节海马突触可塑性中的作用,为进一步深入研究基于海马的结构和功能存在性别差异的机制提供了可靠的线索和依据。
It is well-known that sex differences of structure and function exist between female and male mammalian brain. For example, males have lager volume of the sexually dimorphic nucleus associated with reproduction in hypothalaums than females, and men's abstract thinking is better but women's imagery thinking is better. Hippocampus is an important brain region which has been profoundly invovled in learning and memory, cognition, emotion and stress, sex-specific differences have also been noticed in these hippocampal-dependent structure and physiological function. For example, the size of male hippocampus is slight but significant larger than the females, and the incidence of Alzheimer's disease, a neurological degenerative disease induced by brain aging, is higher in the females than in the males. So far, the molecular mechanisms underlying these sex differences remain unclear. It is known that steroids, such as androgen and estrogens, can regulate hippocampal structure and synaptic plasticity through their nuclear receptors including androgen receptor (AR), estrogen receptor-αand-β(ERa; ERp), but how do these hormones and their receptors regulate sex difference in brain especially hippocampal structure and function is also unclear.
It's clear that the regulation of steroids and their receptors of target gene needs their cofactors including coactivators and corepressors. Steroid receptor coactivator-1(SRC-1) is the most widely distributed steroid receptor coactivator in the brain. It participate the regulation of several kinds of steroid receptors for gene transcription. Studies have shown that SRC-1 gene deficiency results in delayed development of cerebellar Purkinje cells, motor function disorder and significant longer escape latency in Morris maze test. Additionally, infusion SRC-1 antisense nucleotide into hypothalamus significantly changes neural plasticity and reproductive behavior. Previously we have demonstrated high levels of SRC-1 in the adult female rat brain, indicating its multiple function in mediating steroids action in the regulation of brain structure and function. But whether there is any sex difference in the distribution of SRC-1 in the female and male brain and, if so, how about its relationship with brain dimorphism remains to be elucidated.
Hippocampus is the most important functional brain region and deeply affected by circulating and/or local steroids. Some sex differences of the structure and function of hippocampus have been noticed by previous studies. Whether there is any sex difference of SRC-1 expression in the hippocampus during postnatal development and whether this difference is associated with the hippocampal synaptogenesis is not clear. Since sex hormones affect hippocampus in a sex-dependant manner, how about the effects of circulating sex hormones on hippocampal SRC-1 expression and what is the relationship between these effects and hippocampal synaptic plasticity is also unclear.
In order to address these questions, we first used immunohistochemistry to examine the distribution of SRC-1 in the brain of adult female and male mice. Then, we studied the ontogeny of hippocampal SRC-1 and some important synaptic proteins including synaptophysin (SYN), AMPA receptor subtype GluR-1 and postsynaptic density-95 (PSD-95) at different postnatal stages in the female and male mice and explored the correlation between the profile of SRC-1 and synaptic proteins in each sex. Finally, by using the classic steroids-deficiency gonadectomy model to mimic the decline of circular hormone level during aging we examined the expression of hippocampal SRC-1, SYN, GluR-1, PSD-95 at 1-,2- and 4-week after surgery of both sexes and evaluated the correlation of changes between SRC-1 and each synaptic protein.
Main results:
1. SRC-1 immunopositive materials were widely detected in the brain of adult female and male mice. High levels were detected in the olfactory bulb, cerebral cortex, hippocampus, hypothalamus, cerebellum and some nuclei of brainstem. Moderate levels were detected in the thalamus and most nuclei of brainstem, and no or lower levels of SRC-1 were also detected in some specific brain regions.
2. SRC-1 immunopositive materials were predominantly detected in the cell nucleus of mice brain, but in some limited regions associated with motion regulation, it seemed they were also detected in neuritis fiber-like structure of motor root of trigeminal nerve of the brainstem.
3. Male brain showed statistically significant higher levels of SRC-1 immunoreactivities when compared with that of the diestrus females, in very limited regions female brain showed higher levels of SRC-1 immunoreactivities than males but without statistically significance.
4. The expression of SRC-1 in the hippocampus of female was very low at PO.It significantly increased with development and reached the peak at P14, and significantly decreased at P30 and sustained a high level at P60. However, the developmental change of SRC-1 in hippocampus of male was increased from PO to P30, and reached the peak at P30 and then sustained a high level at P60.
5. As to the postnatal developmental profile of hippocampal SYN, GluR-1 and PSD-95, the results showed that females and males shared similar patterns. The levels of SYN and GluR-1 were the lowest at PO but gradually increased with development and reached the peak at P30 and then maintained a high level, levels of PSD-95 were also increased from PO but the peak expression was found at P60.
6. The developmental profile of SRC-1 in hippocampus of female and male mice showed high consistent linear correlation with that of SYN, GluR-1 and PSD-95, respectively, in each sex. The highest correlation was detected between SRC-1/GluR-1 in females and SRC-1/SYN in males.
7. Circulating sex hormones affected hippocampal SRC-1 in a sex-dependant manner, as demonstrated by gonadectomy. Hippocampal SRC-1 levels decreased significantly 2 weeks after ovariectomy but recovered to normal at 4 weeks in females, while in males it decreased right after orchiectomy. GluR-1 showed identical alterations to SRC-1 after gonadectomy,
8. Although hippocampal SYN was not affected by gonadectomy, significant changes of GluR-1 and PSD-95 after gonadectomy were noticed. GluR-1 showed identical changes as that of SRC-1 in both sexes, levels of PSD-95 in female only decreased significantly at 4weeks after ovariectomy but in the males it gradually decreased after orchiectomy.
9. The highest linear correlation was found between SRC-1 and GluR-1 in the female after ovariectomy; and this was found between SRC-1/GluR-1 and SRC-1/PSD-95 after orchiectomy.
Main conclusion:
1. SRC1-is widely distributed in the brain of both female and male mice, significant male-predominance was detected, indicating a multi-function role of SRC-1 in the regulation of various brain function and this sex-dependant distribution may contribute to the sex-difference of some steroid-related brain structure and function.
2. Different extent of sex differences in regarding of the postnatal developmental profiles of hippocampal SRC-1, SYN, GluR-1 and PSD-95 of female and male mice were noticed, correlation analysis showed that SRC-1 is highly related to that of the synaptic proteins, and these results strongly imply a potential role that SRC-1 play in the regulation of hippocampal synaptogenesis in a sex-specific manner.
3. Circulating sex hormones regulate hippocampal SRC-1 in a sex-dependant manner, as demonstrated by gonadectomy. Some synaptic proteins were also regulated by sex hormones as that of SRC-1. Furthermore, correlation analysis revealed that change of SRC-1 is highly with that of some of the synaptic proteins. All these strongly suggest that age-related decrease of SRC-1 may contribute the decreased synaptic plasticity in the hippocampus of female and male mice, in a sex-dependant manner.
In short, the results of our study demonstrate that SRC-1, which widespreads in the brain and expresses differently between females and males, is potentially involved in the regulation of a variety of brain function and mediate the sex difference of brain structure and function. Sex difference in the developmental expression of SRC-1 in hippocampus and being highly correlated with the developmental model of several synaptic proteins suggest the sex difference of SRC-1 may possibly mediate the sex difference of hippocampal synaptogenesis. Moreover, gonad hormones affect hippocampal SRC-1 in a sex-dependant manner, and this change is also highly related with that of these synaptic proteins,implying the sex difference of SRC-1 may further participate in the changes based on sex difference of hippocampal synaptic plasticity and finally effect sex difference of hippocampus-dependent structure and function during the process of aging. Therefore, this study provides some reliable clues for advanced understanding of the mechanisms in sex difference of structure and functions involved in the brain especially in the hippocampus.
引文
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