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5-HT7 receptor activation rescues impaired synaptic plasticity in an autistic-like rat model induced by prenatal VPA exposure
Neurobiology of Learning and Memory ( IF 2.2 ) Pub Date : 2021-05-18 , DOI: 10.1016/j.nlm.2021.107462
Maryam Khodaverdi 1 , Mona Rahdar 2 , Shima Davoudi 2 , Razieh Hajisoltani 2 , Zohreh Tavassoli 3 , Zahra Ghasemi 4 , Aeen Ebrahim Amini 5 , Narges Hosseinmardi 2 , Gila Behzadi 2 , Mahyar Janahmadi 1
Affiliation  

Autism spectrum disorder (ASD) is a severe life-long neuropsychiatric disorder. Alterations and imbalance of several neurochemical systems may be involved in ASD pathophysiology, of them, serotonergic neurotransmission dysfunction and deficiency may underlie behavioral abnormalities associated with ASD. However, the functional importance of serotonergic receptors, particularly 5HT7 receptors in ASD pathology remains poorly defined. Serotonin receptor subtype 7 (5-HT7R) plays a direct regulatory role in the development and also for the mature function of the brain, therefore, further studies are necessary to elucidate the role of these receptors in the etiology of autism. To address this issue, we combined here behavioral, electrophysiological methods to further characterize the contribution of 5-HT7Rs in the prenatal valproic acid (VPA) exposure-induced impairment in synaptic plasticity and their impact on the associated behavioral changes. This may help to unravel the underlying cellular mechanisms involved in ASD and can lead to new treatment and/or prevention therapies based on the role of the serotonergic system for autism.

Findings revealed that compared to control, autistic-like offspring showed increased anxiety-like behavior, reduced social interaction, decreased locomotor activity, and impaired identification of the novel object. However, administration of 5-HT7Rs agonist, LP-211, for 7 consecutive days before testing from postnatal day 21 to 27 reversed all behavioral deficits induced by prenatal exposure to VPA in offspring. Also, both short-term depression and long-term potentiation were impaired in the autistic-like pups, but activation of 5-HT7Rs rescued the LTP impairment in the autistic-like group so that there was no significant difference between the two groups. Blockade of 5-HT7Rs caused LTP impairment following HFS in the autistic-like group. Besides, there was a significant difference in LTD induction following SB-269970 application between the control and the autistic-like groups measured at first 10 min following TPS. Moreover, both the number and the size of retrograde fast blue-labelled neurons in the raphe nuclei were reduced.

Overall, these results provide for the first time, as far as we know, functional evidence for the restorative role of 5-HT7Rs activation against prenatal VPA exposure induced behavioral deficits and hippocampal synaptic plasticity impairment. Therefore, these receptors could be a potential and promising pharmacotherapy target for the treatment of autism.



中文翻译:

5-HT7 受体激活可挽救产前 VPA 暴露诱导的自闭症样大鼠模型中受损的突触可塑性

自闭症谱系障碍(ASD)是一种严重的终生神经精神疾病。ASD 的病理生理学可能涉及多种神经化学系统的改变和失衡,其中,5-羟色胺能神经传递功能障碍和缺乏可能是与 ASD 相关的行为异常的基础。然而,5-羟色胺能受体,特别是 5HT7 受体在 ASD 病理学中的功能重要性仍然不明确。5-羟色胺受体亚型 7 (5-HT7R) 在发育以及大脑的成熟功能中起直接调节作用,因此,需要进一步的研究来阐明这些受体在自闭症病因学中的作用。为了解决这个问题,我们在这里结合了行为,电生理学方法进一步表征 5-HT7R 在产前丙戊酸 (VPA) 暴露引起的突触可塑性损伤中的作用及其对相关行为变化的影响。这可能有助于解开 ASD 所涉及的潜在细胞机制,并可能导致基于 5-羟色胺能系统对自闭症的作用的新治疗和/或预防疗法。

研究结果显示,与对照组相比,自闭症后代表现出焦虑样行为增加、社交互动减少、运动活动减少以及对新物体的识别能力受损。然而,从产后第 21 天到第 27 天测试前连续 7 天施用 5-HT7Rs 激动剂 LP-211 可逆转后代因产前暴露于 VPA 引起的所有行为缺陷。此外,自闭症样幼崽的短期抑郁和长期增强均受损,但 5-HT7Rs 的激活挽救了自闭症样幼崽的 LTP 损伤,因此两组之间没有显着差异。在自闭症组中,5-HT7R 的阻断导致 HFS 后的 LTP 损伤。除了,在 SB-269970 应用后,对照组和自闭症样组在 TPS 后前 10 分钟测量的 LTD 诱导存在显着差异。此外,中缝核中逆行快速蓝色标记的神经元的数量和大小都减少了。

总的来说,据我们所知,这些结果首次提供了功能性证​​据,证明 5-HT7Rs 激活对产前 VPA 暴露引起的行为缺陷和海马突触可塑性损伤具有恢复作用。因此,这些受体可能是治疗自闭症的潜在和有希望的药物治疗靶点。

更新日期:2021-06-25
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