P262 Mechanisms of bistability in spinal motoneurons and its regulation
Ilya A. Rybak*1, Yaroslav I. Molkov2, Thomas Stell2, Florent Krust3, Frédéric Brocard3
1 Department of Neurobiology and Anatomy, Drexel University College of Medicine,
Philadelphia, PA, USA
2 Department of Mathematics and Statistics and Neuroscience Institute, Georgia State
University, Atlanta, GA, USA
3 Institut de Neurosciences de la Timone, Aix Marseille University, CNRS, Marseille, France
*Email: rybak@drexel.edu
Introduction
Spinal motoneurons represent output elements of spinal circuitry that activate skeletal muscles to produce motor behaviors. Firing behavior of many motoneurons is characterized by bistability allowing them to maintain a self-sustained spiking activity initiated by a brief excitation and stopped by a brief inhibition. Serotonin can induce or amplify bistability, influencing motor behaviors. Biophysical mechanisms of bistability involve nonlinear interactions of specific ionic currents. Experimental studies identified ionic currents linked to bistability [1,2]. Using computational modeling, we simulate motoneuronal bistability and analyze the roles of key ionic currents in its generation and regulation.
Methods
We have developed a conductance-based mathematical model of spinal motoneuron to explore and analyze the role of different ionic currents and their interactions in generation and control of motoneuronal bistability under different conditions. The one-compartmental model includes main spike-generating currents, fast sodium (INaF) and potassium rectifier (IKdr), as well as persistent sodium (INaP), slowly inactivating potassium (IKv1.2aka potassium A,IKA), high-voltage activated calcium (ICaL), Ca2+-activated cation non-specific (ICAN), and Ca2+-dependent potassium (IKCa, associated with SK channels) currents. Additionally, the model incorporates the intracellular Ca2+dynamics including calcium-induced calcium release mechanism (CICR).
Results
Our simulations show that bistability in motoneurons relies onICAN, activated by intracellular Ca2+accumulated byICaLand the CICR mechanism. Two other currents play modulatory roles withINaPaugmenting bistability andIKCaattenuating or abolishing it. The interplay betweenICANandIKCashapes the membrane potential dynamics, producing post activation afterdepolarization (ADP) or afterhyperpolarization (AHP), withIKv1.2modulating the membrane potential dynamics. Under certain conditions (such as an elevated extracellular K+concentration),INaPcan sustain bistability independently ofICAN.
Discussion
Our findings clarify the ionic basis of motoneuron bistability, underscoring its reliance on current interactions and external conditions, and offer insights into motor function and potential therapeutic strategies for motor disorders. Our results suggest that serotonin can induce or increase motoneuron bistability by amplifyingICAN(e.g., via increased intracellular Ca2+concentration due to an increasedICaLor via 5-HT3 receptors), activation ofINaPor suppression ofIKCa(both through 5-HT2 receptors).
Acknowledgements
No
References
● Harris-Warrick, R.M., Pecchi, E., Drouillas, B., Brocard, F., & Bos R. (2024). Effect of size on expression of bistability in mouse spinal motoneurons. Journal of Neurophysiology, 131(4), 577-588.https://doi.org/10.1152/jn.00320.2023.
● Bos, R., Drouillas, B., Bouhadfane, M., Pecchi, E., Trouplin, V., Korogod, S.M., & Brocard, F. (2021) Trpm5 channels encode bistability of spinal motoneurons and ensure motor control of hindlimbs in mice. Nature Communication, 12(1), 6815.https://doi.org/10.1038/s41467-021-27113-x.
