Cell . . . Qian Yongyou/Li Boxing teamed up to discover the regulatory mechanism of neuronal excitatory steady state.

Homeostasis refers to a state in which the body maintains its relative stability.in the nervous system, synaptic transmission and excitability of neurons also have steady-state regulation, which is called the homeostatic plasticity of the nervous system.when the synaptic transmission or excitability of neurons changes continuously, the cells will induce the synaptic transmission or excitability to adjust in the opposite direction to the original changes, so as to maintain the synaptic transmission or excitability at a relatively stable level, so as to ensure the normal information transmission of neurons and neural circuits (Fig. 1) [1,2].Fig. 1. Steady state plasticity of neurons.excerpted from references (1) the steady-state plasticity of neurons is involved in many important physiological functions. For example, during the wake-up sleep cycle, neuronal discharge changes continuously, which can regulate the structure and function of synapses through steady-state plasticity [3,4].the abnormality of steady-state plasticity is also related to autism and other neurological / mental diseases. For example, the abnormality of steady-state plasticity in the autism mouse model is considered to be one of the molecular mechanisms of autism [5-9].steady state plasticity was discovered by Gina turrigiano and Eve Marder et al. In the 1990s [10,11], a lot of studies have been carried out on it. However, at the molecular mechanism level, the research mainly focuses on synaptic homeostasis, while the research on excitatory homeostasis has been neglected.on June 2, 2020, Li boxing Laboratory of Sun Yat sen University and Richard W. Tsien Laboratory of New York University published the article "nervous activity co OPS LTP machine to drive potassium channel splitting and homeostatic spike Widening" in cell magazine, and found the molecular mechanism of excitatory homeostasis regulation.the research group used sodium channel blocker (TTX) to block action potential to simulate the long-term decrease of neuronal excitability.after TTX was removed, the action potential duration was significantly prolonged and the excitability compensation of neurons was increased, which indicated that there was a steady-state regulation of excitability in neurons.further studies revealed that the above regulation of excitatory homeostasis was due to the decreased selective mRNA cleavage of potassium channel (BK channel) mediated by Nova-2.it is worth noting that when TTX is used for a long time, although the cell body of neurons does not produce action potential, the synapses of neurons produce obvious depolarization, which is enough to activate L-type calcium channels at synapses.the latter transmits information to the nucleus through calmodulin kinases (β CaMKK and CaMKIV) downstream, causing Nova-2 phosphorylation and extranuclear migration, resulting in the decrease of BK channel mRNA selective splicing mediated by the latter (Fig. 2).the above studies provide a complete demonstration of the "steady state feedback loop" hypothesis proposed nearly 30 years ago (lemasson et al., 1993; Marder et al., 1996; Siegel et al., 1994) (Fig. 3).multiple molecules in the above signaling pathways (AMPA receptor, L-type calcium channel, calmodulin kinase family, Nova-2, BK channel) are closely related to autism, schizophrenia, depression and other neuro / psychiatric diseases, suggesting that the abnormality of the pathway may be involved in the pathogenesis of the above-mentioned diseases. G. turrigiano, homestatic synthetic plasticity: local and global mechanisms for stabilizing neural function. Cold Spring Harbor perspectives in biology 4, a005736 (2012). 2. G. g. turrigiano, the dialect of Hebb and homeostasis. Philos trans r SOC long b bio SCI 372,(2017).3. G. H. Diering, R. S. Nirujogi, R. H. Roth, P. F. Worley, A. Pandey, R. L. Huganir, Homer1a drives homeostatic scaling-down of excitatory synapses during sleep. Science 355, 511-515 (2017).4. K. B. Hengen, A. Torrado Pacheco, J. N. McGregor, S. D. Van Hooser, G. G. Turrigiano, Neuronal Firing Rate Homeostasis Is Inhibited by Sleep andPromoted by Wake. Cell 165, 180-191 (2016).5. C. Mullins, G. Fishell, R. W. Tsien, Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops. Neuron 89, 1131-1156 (2016).6. Z. Qiu, E. L. Sylwestrak, D. N. Lieberman, Y. Zhang, X. Y. Liu, A. Ghosh, The Rett syndrome protein MeCP2 regulates synaptic scaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 32, 989-994 (2012).7. M. E. Soden, L. Chen, Fragile X protein FMRP is required for homeostatic plasticity and regulation of synaptic strength by retinoic acid. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 16910-16921 (2010).8. J. Wondolowski, D. Dickman, Emerging links between homeostatic synaptic plasticity and neurological disease. Front Cell Neurosci 7, 223 (2013).9. V. Tatavarty, A. Torrado Pacheco, C. Groves Kuhnle, H. Lin, P. Koundinya, N. J. Miska, K. B. Hengen, F. F. Wagner, S. D. Van Hooser, G. G. Turrigiano, Autism-Associated Shank3 Is Essential for Homeostatic Compensation in Rodent V1. Neuron,  (2020).10. G. Turrigiano, L. F. Abbott, E. Marder, Activity-dependent changes in the intrinsic properties of cultured neurons. Science 264, 974-977 (1994).11. G. G. Turrigiano, K. R. Leslie, N. S. Desai, L. C. Rutherford, S. B. Nelson, Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391, 892-896 (1998).