前脑谷氨酸能神经元缺乏 Cacna1c 会改变雌性小鼠的行为和海马可塑性。

IF 5.8 1区 医学 Q1 PSYCHIATRY
Srivaishnavi Loganathan, Danusa Menegaz, Jan Philipp Delling, Matthias Eder, Jan M Deussing
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引用次数: 0

摘要

编码 L 型电压门控钙通道(LTCC)Cav1.2 α1 亚基的 CACNA1C 与多种精神疾病有关。临床研究发现,CACNA1C 风险等位基因携带者的行为以及大脑结构和功能都发生了改变。Cav1.2 缺乏症的啮齿类动物模型也证实了这些研究结果,该模型显示焦虑、认知和社交障碍增加,并转向积极的压力应对策略。这些行为改变伴随着功能缺陷,如长期电位(LTP)降低和兴奋/抑制(E/I)失衡。然而,这些临床前研究主要局限于雄性啮齿动物,很少有研究探讨性别特异性效应。在这里,我们研究了雌性条件性基因敲除(CKO)小鼠前脑谷氨酸能神经元中 Cav1.2 缺失的影响。CKO小鼠在新环境中表现出过度运动、焦虑相关行为增加、认知障碍和主动压力应对行为增加。这些行为改变既不受发情周期阶段的影响,也不受Nex/Neurod6单倍体缺失或Cre表达的影响,这与利用Nex-Cre驱动系条件性失活Cacna1c有内在联系。在海马中,Cav1.2失活增强了突触前的成对脉冲促进,而不会改变CA3-CA1突触的突触后LTP。此外,雌性 CKO 小鼠的 CA1 锥体神经元显示出树突复杂性和棘密度的降低。总之,我们的研究结果扩展了现有的知识,表明依赖于Cav1.2的结构和功能改变是雌性Cav1.2-Nex小鼠行为改变的可能机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cacna1c deficiency in forebrain glutamatergic neurons alters behavior and hippocampal plasticity in female mice.

CACNA1C, coding for the α1 subunit of L-type voltage-gated calcium channel (LTCC) Cav1.2, has been associated with multiple psychiatric disorders. Clinical studies have revealed alterations in behavior as well as in brain structure and function in CACNA1C risk allele carriers. These findings are supported by rodent models of Cav1.2 deficiency, which showed increased anxiety, cognitive and social impairments as well as a shift towards active stress-coping strategies. These behavioral alterations were accompanied by functional deficits, such as reduced long-term potentiation (LTP) and an excitation/inhibition (E/I) imbalance. However, these preclinical studies are largely limited to male rodents, with few studies exploring sex-specific effects. Here, we investigated the effects of Cav1.2 deficiency in forebrain glutamatergic neurons in female conditional knockout (CKO) mice. CKO mice exhibited hyperlocomotion in a novel environment, increased anxiety-related behavior, cognitive deficits, and increased active stress-coping behavior. These behavioral alterations were neither influenced by the stage of the estrous cycle nor by the Nex/Neurod6 haploinsufficiency or Cre expression, which are intrinsically tied to the utilization of the Nex-Cre driver line for conditional inactivation of Cacna1c. In the hippocampus, Cav1.2 inactivation enhanced presynaptic paired-pulse facilitation without altering postsynaptic LTP at CA3-CA1 synapses. In addition, CA1 pyramidal neurons of female CKO mice displayed a reduction in dendritic complexity and spine density. Taken together, our findings extend the existing knowledge suggesting Cav1.2-dependent structural and functional alterations as possible mechanisms for the behavioral alterations observed in female Cav1.2-Nex mice.

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来源期刊
CiteScore
11.50
自引率
2.90%
发文量
484
审稿时长
23 weeks
期刊介绍: Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.
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