Review
Physiology
Jessica C. Pressey, Miranda de Saint-Rome, Vineeth A. Raveendran, Melanie A. Woodin
Summary: Synaptic inhibition plays a crucial role in regulating neuronal excitability, which depends on the neurotransmitters GABA and glycine and their effects on the Cl- gradient. CCCs, specifically NKCC1 and KCC2, regulate the Cl- gradient in neurons and play a critical role in healthy brain function. Understanding the mechanisms of CCC regulation and their impact on inhibitory synaptic plasticity can provide insights into neurological disorders. Techniques for estimating and recording intracellular Cl- can be useful for researchers interested in studying CCCs and neuronal excitability. Additionally, nonneuronal cells regulate neuronal excitability by modulating Cl- levels, and CCC-mediated alterations in neuronal excitability are implicated in neurological disorders.
PHYSIOLOGICAL REVIEWS
(2022)
Review
Behavioral Sciences
Carlijn Peerboom, Corette J. Wierenga
Summary: The transition from depolarizing to hyperpolarizing GABA signaling during postnatal development is crucial for brain function and associated with neurodevelopmental disorders. Each developmental shift in GABA function regulates different aspects of neuron development, ensuring alignment with the developing network environment. Proper timing of the postnatal GABA shift may be influenced by sensory input and a developmental perspective is needed to understand the consequences of mismatches in connectivity, activity, and GABA signaling during brain development.
NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
(2021)
Article
Cell Biology
Rebecca Jarvis, Shu Fun Josephine Ng, Anna J. Nathanson, Ross A. Cardarelli, Krithika Abiraman, Fergus Wade, Aidan Evans-Strong, Marina P. Fernandez-Campa, Tarek Z. Deeb, Joshua L. Smalley, Tanguy Jamier, Ian K. Gurrell, Lisa McWilliams, Aarti Kawatkar, Leslie C. Conway, Qi Wang, Roland W. Burli, Nicholas J. Brandon, Iain P. Chessell, Aaron J. Goldman, Jamie L. Maguire, Stephen J. Moss
Summary: Activation of KCC2 can reduce benzodiazepine-resistant seizures and decrease associated neuronal damage.
CELL REPORTS MEDICINE
(2023)
Article
Clinical Neurology
Iason Keramidis, Brendan B. Mcallister, Julien Bourbonnais, Feng Wang, Dominique Isabel, Edris Rezaei, Romain Sansonetti, Phil Degagne, Justin P. Hamel, Mojtaba Nazari, Samsoon Inayat, Jordan C. Dudley, Annie Barbeau, Lionel Froux, Marie-Eve Paquet, Antoine G. Godin, Majid H. Mohajerani, Yves De Koninck
Summary: In mouse models carrying Alzheimer's disease-related mutations, a loss of neuronal membrane KCC2, responsible for maintaining GABA(A)-mediated inhibition, occurs in the hippocampus and prefrontal cortex before symptoms appear. Downregulation of KCC2 is inversely correlated with the age-dependent increase in amyloid-beta 42. Restoring KCC2 function can protect against cognitive decline and memory deficits associated with Alzheimer's disease.
Article
Biochemistry & Molecular Biology
Wenlin Liao, Kun-Ze Lee
Summary: Cyclin-dependent kinase-like 5 (CDKL5) is an important regulator in neuronal development and function. Patients with CDKL5 deficiency disorder (CDD) often present with early-onset epilepsy. However, mouse models of CDD have not shown spontaneous seizures. In this study, the researchers found that mice lacking CDKL5 exhibited spontaneous epileptic EEG discharges at postnatal day 12, but these spikes disappeared after postnatal day 14. Transcriptome profiling revealed age-dependent and brain region-specific alterations of gene expression. These findings provide new insights into the etiology of CDD and potential targets for the treatment of neonatal epilepsy.
HUMAN MOLECULAR GENETICS
(2023)
Article
Multidisciplinary Sciences
Xianchun Lan, Song Ding, Tianzhe Zhang, Ying Yi, Conghui Li, Wenwen Jin, Jian Chen, Kaiwei Liang, Hengbin Wang, Wei Jiang
Summary: This study reveals that PCGF6 plays a crucial role in determining the lineage specification of human pluripotent stem cells by promoting neuroectoderm differentiation and repressing mesendoderm differentiation. The activation of the SOX2 gene and the repression of the WNT/beta-catenin signaling pathway are key mechanisms involved in this process.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Alex Penev, Andrew Bazley, Michael Shen, Jef D. Boeke, Sharon A. Savage, Agnel Sfeir
Summary: Telomere length control is crucial for cellular lifespan and tumor suppression, with telomerase activation primarily driven by alternative splicing events centered around hTERT exon 2. The study highlights the critical role of hTERT alternative splicing in developmental regulation of telomerase in pluripotent cells, implicating defective splicing in telomere biology disorders.
Review
Chemistry, Multidisciplinary
Erin McMoneagle, Jin Zhou, Shiyao Zhang, Weixue Huang, Sunday Solomon Josiah, Ke Ding, Yun Wang, Jinwei Zhang
Summary: Epilepsy is a neurological disorder characterized by seizures, and impaired function of the KCC2 protein has been found to contribute to its pathogenesis. Enhancing KCC2 activation and regulating its phosphorylation and transcription have shown promising results in attenuating seizure severity. Recent advances in understanding the regulatory mechanisms of KCC2 have led to the discovery of novel small molecules that modulate its activity, making it a potential therapeutic target for treating epilepsy.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Multidisciplinary Sciences
Sarah M. Lloyd, Daniel B. Leon, Mari O. Brady, Deborah Rodriguez, Madison P. McReynolds, Junghun Kweon, Amy E. Neely, Laura A. Blumensaadt, Patric J. Ho, Xiaomin Bao
Summary: In this study, the researchers found that the Super Elongation Complex (SEC) controls fate decisions of progenitor cells by suppressing a group of rapid response genes. The repressive role of SEC depends on the AFF1 scaffold, but not AFF4. The expression of these rapid response genes is regulated by CDK9 activity. The findings suggest that the activity switch of SEC-associated CDK9 is a key initial process in determining the fate of progenitor cells.
NATURE COMMUNICATIONS
(2022)
Article
Clinical Neurology
Siddharth Banka, Abigail Bennington, Martin J. Baker, Ellen Rijckmans, Giuliana D. Clemente, Nurhuda Mohamad Ansor, Hilary Sito, Pritha Prasad, Kwame Anyane-Yeboa, Lauren Badalato, Boyan Dimitrov, David Fitzpatrick, Anna C. E. Hurst, Anna C. Jansen, Melissa A. Kelly, Ian Krantz, Claudine Rieubland, Meredith Ross, Natasha L. Rudy, Javier Sanz, Katrien Stouffs, Zhuo Luan Xu, Angeliki Malliri, Marcelo G. Kazanietz, Tom H. Millard
Summary: RAC1 is a crucial GTPase involved in neurodevelopmental disorders. This study reveals that certain variants in RAC1 can activate downstream signaling pathways, leading to abnormal neuronal morphology and a distinct neurodevelopmental disorder.
Article
Neurosciences
Adya Saran Sinha, Tianying Wang, Miho Watanabe, Yasushi Hosoi, Eisei Sohara, Tenpei Akita, Shinichi Uchida, Atsuo Fukuda
Summary: The role of WNK3 in regulating intracellular Cl- concentration and excitability of neurons is still unclear. In this study, WNK3 knockout mice were used to investigate the effects of WNK3 on Cl- concentration and excitability of pyramidal neurons in the prefrontal cortex. The results showed that WNK3 knockout led to an increase in Cl- concentration and a decrease in excitability of neurons. Further experiments revealed that WNK3 is closely linked with the KCC2 channel in the regulation of resting K+ conductance.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Sandy Al Hayek, Ahmad Alsawadi, Zakaria Kambris, Jean-Philippe Boquete, Jerome Bohere, Clement Immarigeon, Brice Ronsin, Serge Plaza, Bruno Lemaitre, Francois Payre, Dani Osman
Summary: The research uncovers a cell-intrinsic role of the OvoL family transcription factor Shavenbaby (Svb) in balancing self-renewal and differentiation of Drosophila intestinal stem cells, mediated by the downstream target of Wnt and EGFR pathways. The switch between Svb repressor and activator is triggered by systemic steroid hormone, adjusting stem cell proliferation versus differentiation and suggesting a broad role of OvoL/Svb in adult and cancer stem cells.
Article
Cell Biology
Tomi Tuomainen, Nikolay Naumenko, Maija Mutikainen, Anastasia Shakirzyanova, Sarah Sczelecki, Jennifer L. Estall, Jorge L. Ruas, Pasi Tavi
Summary: Non-canonical isoforms of PGC-1 alpha are expressed in the heart and can induce specific cardiac phenotypes through cellular signaling pathways. These findings reveal the different biological roles of PGC-1 alpha isoforms, which should be taken into account in future therapeutic developments.
Article
Biochemistry & Molecular Biology
Dong Kyu Kim, Hyobin Jeong, Jingi Bae, Moon-Yong Cha, Moonkyung Kang, Dongjin Shin, Shinwon Ha, Seung Jae Hyeon, Hokeun Kim, Kyujin Suh, Mi-Sun Choi, Hoon Ryu, Seong-Woon Yu, Jong-Il Kim, Yeon-Soo Kim, Sang-Won Lee, Daehee Hwang, Inhee Mook-Jung
Summary: This study reveals the crucial role of mitochondria in neural progenitors and their association with the protein amyloid-beta, which is linked to Alzheimer's disease. Mitochondrial dysfunction inhibits neuronal differentiation, leading to deficits in adult hippocampal neurogenesis and cognitive function. The research suggests that lysine demethylase 5A epigenetically suppresses differentiation in response to mitochondrial damage.
EXPERIMENTAL AND MOLECULAR MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Michihiro Toritsuka, Hiroki Yoshino, Manabu Makinodan, Daisuke Ikawa, Sohei Kimoto, Kazuhiko Yamamuro, Kazuya Okamura, Wado Akamatsu, Yohei Okada, Takuya Matsumoto, Kazumichi Hashimoto, Yoichi Ogawa, Yasuhiko Saito, Kyosuke Watanabe, Chieko Aoki, Ryohei Takada, Shin-ichi Fukami, Kaori Hamano-Iwasa, Hideyuki Okano, Toshifumi Kishimoto
Summary: The study utilized human induced pluripotent stem cells (hiPSCs) to investigate the pathophysiology of schizophrenia. It revealed that neurons derived from hiPSCs of a schizophrenia patient exhibited higher frequency of spontaneous excitatory activity compared to the control, despite similar synaptic formation. Alterations in the expression pattern of KCC2 in these neurons may contribute to understanding the pathology of schizophrenia in the developing nervous system.
NEUROCHEMISTRY INTERNATIONAL
(2021)