CAMK2A

Major depressive disorder (MDD) is a widespread mental health condition that for many is disabling. It has long been appreciated that MDD has genetic as well as environmental influences. In a new study researchers identify a gene that interacted with stress to mediate aspects of treatment-resistant MDD in an animal model. Major depressive disorder (MDD) is a widespread mental health condition that for many is disabling. It has long been appreciated that MDD has genetic as well as environmental influences. In a new study in Biological Psychiatry, published by Elsevier, researchers identify a gene that interacted with stress to mediate aspects of treatment-resistant MDD in an animal model. Jing Zhang, PhD, at Fujian Medical University and senior author of the study, said, "Emerging evidence suggests that MDD is a consequence of the co-work of genetic risks and environmental factors, so it is crucial to explore how stress exposure and risk genes co-contribute to the pathogenesis of MDD." To do that, the authors used a mouse model of stress-induced depression called chronic social defeat stress (CSDS) in which mice are exposed to aggressor mice daily for two weeks. They focused on a gene called LHPP, which interacts with other signaling molecules at neuronal synapses. Increased expression of LHPP in the stressed mice aggravated the depression-like behaviors by decreasing expression of BDNF and PSD95 by dephosphorylating two protein kinases, CaMKIIα and ERK, under stress exposure. Dr. Zhang noted, "Interestingly, LHPP mutations (E56K, S57L) in humans can enhance CaMKIIα/ERK-BDNF/PSD95 signaling, which suggests that carrying LHPP mutations may have an antidepressant effect in the population." MDD is an extremely heterogeneous condition. Differences in the types of depression experienced by people influence the way they respond to treatment. A large subgroup of people with depression fail to respond to standard antidepressant medications and have "treatment-resistant" symptoms of depression. These patients often respond to different medications, such as ketamine or esketamine, or to electroconvulsive therapy. Notably, esketamine markedly alleviated LHPP-induced depression-like behaviors, whereas the traditional drug fluoxetine did not, suggesting that the mechanism might underlie some types of treatment-resistant depression. John Krystal, MD, Editor of Biological Psychiatry, said of the work, "We have limited understanding of the neurobiology of treatment-resistant forms of depression. This study identifies a depression risk mechanism for stress-related behaviors that fail to respond to a standard antidepressant but respond well to ketamine. This may suggest that the risk mechanisms associated with the LHPP gene shed light on the poorly understood biology of treatment-resistant forms of depression." Dr. Zhang added, "Together, our findings identify LHPP as an essential player driving stress-induced depression, implying targeting LHPP as an effective strategy in MDD therapeutics in the future."

癫痫是一种常见的神经系统疾病，以自发性和反复发作为特征，全球有7000万人受到影响。其中，颞叶癫痫(TLE)是最常见的癫痫类型，现有的抗癫痫药物无法很好地控制TLE。 癫痫是一种常见的神经系统疾病，以自发性和反复发作为特征，全球有7000万人受到影响。其中，颞叶癫痫(TLE)是最常见的癫痫类型，现有的抗癫痫药物无法很好地控制TLE。TLE常伴有认知损害，在病变方面与TLE有许多共同的特征，包括颞叶区域的神经元丢失和硬化。 临床数据显示，癫痫患者发生痴呆症的风险是非癫痫患者的2.5倍。同样，癫痫样异常在阿尔茨海默病患者中更常见。患有TLE的老年人和轻度认知障碍的人表现出类似的症状，如语言衰退、记忆障碍和脑萎缩。不幸的是，认知性并存往往无法诊断，也没有有效的治疗策略来改善癫痫患者的认知功能减退。因此，揭示TLE相关认知损害的机制对于开发精确的治疗方法至关重要。 图片来源：https://doi.org/10.1038/s41401-023-01129-z 近日，来自浙江中医药大学的研究者们在Acta Pharmacologica Sinica杂志上发表了题为“Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model”的文章，该研究结果表明，癫痫发作激活神经元参与了TLE的认知损害，提示癫痫发作激活神经元是减轻TLE认知损害的潜在治疗靶点。 认知障碍是颞叶癫痫(TLE)的常见共病，目前的治疗方法并不能很好地控制认知障碍。癫痫发作如何影响认知表现在很大程度上仍不清楚。在这项研究中，研究者研究了癫痫发作下激活神经元在TLE认知损害中的作用。 研究者将双极电极植入雄性小鼠海马CA3区，用于点燃刺激和记录脑电；使用带有增强型突触活性反应元件(E-sARE)的特殊启动子标记下丘脑束下癫痫激活神经元；采用化学遗传学方法操纵下丘脑癫痫发作激活神经元的活动；评估对象位置记忆(OLM)和新对象识别(NOR)任务中的认知功能。 本研究发现抑制癫痫发作激活的神经元(主要是CaMKIIα+谷氨酸能神经元)可以减轻癫痫发作的泛化和改善认知能力，但抑制癫痫发作激活的GABA能中间神经元对癫痫发作和认知能力没有影响。 相比之下，在基础状态下，抑制整个下丘脑CaMKIIα+神经元会损害幼稚小鼠的认知功能。值得注意的是，通过增加认知任务中的神经兴奋性，抑制丘脑下部癫痫发作激活神经元的化学发生增强了认知反应性c-fos+神经元的招募。 抑制癫痫发作激活神经元的化学生成可以减轻癫痫发作的泛化 图片来源：https://doi.org/10.1038/s41401-023-01129-z 综上所述，本研究结果阐明了癫痫相关认知功能障碍的亚核机制，并支持亚核下癫痫激活神经元作为减轻TLE认知损害的潜在靶点。然而，本结果表明，这种E-sARE标记技术的特异性和效率是有限的，这可能会影响对结果的解释。 由于他莫昔芬的半衰期(几小时)远长于标记发作事件的持续时间(几分钟)，DREADDS不仅在癫痫发作激活的下丘脑神经元中表达，而且在其他一些事件激活的神经元中也表达，如发作间期状态激活的神经元。未来，能够更准确地控制Cre-重组酶表达时间窗的药物可能能够解决这一困境。（生物谷 Bioon.com） 参考文献 Lin Yang et al. Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model. Acta Pharmacol Sin. 2023 Jul 25. doi: 10.1038/s41401-023-01129-z.

KANAZAWA, Japan, July 3, 2023 /PRNewswire/ -- Researchers at Kanazawa University report in Science Advances high-speed atomic force microscopy experiments that show the structural and chemical changes in an enzyme thought to play a vital role in modulating the strength of neural connections. Synapses connect neurons allowing the transmission of signals around the neural network. The strength of these connections varies – for instance strengthening or weakening depending on the signals received and how. This synaptic 'plasticity' underlies learning and memory, and the Ca2+/calmodulin-dependent protein kinase II (CaMKII) is known to play a key role. Previous studies have provided some clues to the mechanisms of CaMKII protein activity in these functions but no one had seen these proteins in action. Now, Hideji Murakoshi at the Graduate University of Advanced Studies and the National Institute for Physiological Sciences and Mikihiro Shibata at Kanazawa University and their colleagues have used high speed atomic force microscopy (HS-AFM) to observe the structural dynamics of these proteins for the first time, not only in various states but in three different species. CaMKII is common to a vast range of species from mammals like rats to older, non-mammalian species like the roundworms (C. elegans) and hydra. In particular, certain structural features of the protein are particularly well preserved, including the kinase domain, the regulatory segment that inhibits the activity of the kinase domain and the hub domain. In addition, the protein has binding sites, phosphorylation sites and linker regions; however, the linker region shows a little more variability suggesting that its function and activation mechanisms are more bespoke for the different species. Previous studies had suggested that the regulatory segment's inhibition of the kinase domain is released when Ca2+/calmodulin binds to the regulatory segment. The activated kinase domains then phosphorylate each other, activity that persists even after the Ca2+/calmodulin becomes dissociated, which has been 'hypothesized to be a form of molecular memory', as the researchers describe in their report. Murakoshi, Shibata and their colleagues studied the protein using atomic force microscopy, which feels topologies using a nanoscale tip, like a needle reading a vinyl record, raster scanning the image plane to build up a picture of the sample structure. With HS-AFM, these images are collected quickly enough to record movies of how these structures change. The researchers noted various measures of the proteins size and motion – the gyrus of rotation – as well as reactions such as kinase domain oligomerization (that is, where there is a limited level of polymerization to join molecules into chains) and phosphorylation – the addition of a phosphoryl group (PO3), which can activate enzymes like kinase. They found that the kinase domain was quite mobile, although this decreased with Ca2+/calmodulin binding. The researchers explain this in terms of the binding stabilizing the protein into a particular helical structure called an α helix. They also note that the binding causes the protein to extend 3nm from the hub assembly, which they suggest may be what dissociates the regulatory segment from the active site in the kinase domain. The mobility then increases again with phosphorylation, which the researchers attribute to the protein losing some of the order of the helical structure. Of the three species investigated – the rat, roundworm and hydra – Murakoshi, Shibata and their colleagues found that the kinase domain only oligomerized in the rat. In addition, in the rat, the protein was more resilient to phosphatase, which removes phosphate groups (PO4) from proteins. "In conclusion," they report, "Our findings provide a basis for a deeper understanding of the molecular mechanisms of CaMKIIα activation." Related image Caption High-speed atomic force microscopy image of calmodulin-dependent protein kinase II. This image was taken at 3.3 frames/second. © 2023 Tsujioka, et al., Science Advances. Glossary High-speed atomic force microscope Atomic force microscopy (AFM) 'feels' the topography of surfaces by the increase and decrease of surface forces tugging on a nanoscale tip as changes in surface height change the distance between the tip and the surface. The tip is mounted on a cantilever so that the tiny changes in the force can be read out by the resulting deflection in the cantilever. AFM can resolve structures with subnanometre scale resolution. It has particular advantages for biological studies because it does not require conducting substrates or a current, which are requirements for other primary microscopes with comparable resolutions, such as the scanning tunnelling microscope. For a long time AFM was limited by the time it takes to capture an image of the surface, but this changed when Toshio Ando at Kanazawa University revealed how the tool could be upgraded to high-speed AFM using various modifications to the scanning, deflection detection and other electronic devices, as well as specifications for the cantilever. With high-speed AFM it became possible to capture dynamics at the nanoscale for the first time. Ca2+/calmodulin-dependent protein kinase II Protein kinases are enzymes. They use phosphate sourced from ATP to phosphorylate specific amino acids on target proteins, which leads to changes in the protein's conformation that regulate its biological activity. Ca2+/calmodulin-dependent protein kinase II (CaMK II) is a serine/threonine specific protein kinase, which means it phosphorylates the OH groups on the serine or threonine amino acid residues. It is modulated by Ca2+/calmodulin where calmodulin is simply an abbreviation for calcium modulated protein. The type two Ca2+/calmodulin-dependent protein kinases are multifunctional and are involved in neurotransmitter secretion, transcription factor regulation, and glycogen metabolism. Reference Shotaro Tsujioka, Ayumi Sumino, Yutaro Nagasawa, Takashi Sumikama, Holger Flechsig, Leonardo Puppulin, Takuya Tomita, Yudai Baba, Takahiro Kakuta, Tomoki Ogoshi, Kenichi Umeda, Noriyuki Kodera, Hideji Murakoshi, Mikihiro Shibata. Imaging single CaMKII holoenzymes at work by high-speed atomic force microscopy, Science Advances June 2023. DOI： 10.1126/sciadv.adh1069 URL: Contact Hiroe Yoneda Senior Specialist in Project Planning and Outreach NanoLSI Administrative Office WPI Nano Life Science Institute (WPI-NanoLSI) Kanazawa University Kakuma-machi, Kanazawa 920-1192, Japan Email: [email protected] Tel: +81 (76) 234-4550 About Nano Life Science Institute (WPI-NanoLSI) Nano Life Science Institute (NanoLSI), Kanazawa University is a research center established in 2017 as part of the World Premier International Research Center Initiative of the Ministry of Education, Culture, Sports, Science and Technology. The objective of this initiative is to form world-tier research centers. NanoLSI combines the foremost knowledge of bio-scanning probe microscopy to establish 'nano-endoscopic techniques' to directly image, analyze, and manipulate biomolecules for insights into mechanisms governing life phenomena such as diseases. About Kanazawa University As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities. The University is located on the coast of the Sea of Japan in Kanazawa – a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas. SOURCE Kanazawa University