Axon Physiology in the CNS

     Axon is a part of neuron which generates and propagates action potentials towards the presynaptic terminals. Due to robust regenerative nature, the axonal action potentials are thought of as stable binary code for rich and ultrafast neuronal computation in the brain. We focus on to study the dynamic control of the excitability of the axons, to reveal the general rules governing the neuronal signaling supporting the complex brain functions. 

Our approach

     To study the axonal spike signaling with a high temporal resolution, we adopted direct electrophysiological recordings from the single axon terminals of mouse hippocampal mossy fibers, the best-studied axons in the CNS. We also often use numerical computation using the realistic model of the mossy fiber axons, the best-model of CNS axons thus far, to test for quantitative validation of the experimental findings. 

Achievement

Small depolarization assists stimulus-induced ectopic burst in hippocampal mossy fiber

   Strong repetitive stimuli often induce burst discharges of ectopic origin. Although hyperpolarization-activated cation channels (Ih) have been shown to serve a central role, additional mechanisms are supposed to assist the ectopic burst generation. In this study, the underlying mechanisms were explored using computational simulations. Inactivating properties of axonal potassium channels also assist ectopic burst.  

     Front Cell Neurosci 2025    DOI: https://doi.org/10.3389/fncir.2024.1505204

          ModelDB 2025　 #2018003    https://modeldb.science/2018003 

Blockade of potassium channel induces an ectopic burst of hippocampal mossy fiber

    Application of a potassium channel blocker 4-AP to the hippocampal slice preparations induces burst firings when applied to the hippocampal slice preparations. In this study, the underlying mechanisms were explored using direct recordings from the single hippocampal mossy fiber terminals and mathematical simulations. Burst firings were supposed to be generated ectopically from the distal axons.

     Front Cell Neurosci 2024    DOI: https://doi.org10/3389/fncel.2024.1434165

          ModelDB 2024　 #20155771    https://modeldb.science/2015571 

Roles of inactivating potassium channels in short-term synaptic plasticity

     Axonal potassium channels in the brain often display inactivation different from those found in squid giant axons. Using simulation approaches, we demonstrated that accumulated inactivation of potassium channels during repetitive stimulation assisted large short-term plasticity in addition to the classical residual potassium mechanism.

     Front Cell Neurosci 2023    DOI: https://doi.org/10.3389/fncel.2023.1154910

          ModelDB 2023　 #267617    https://modeldb.science/267617

Mechanisms of analog tuning by axonal subthreshold voltage signaling

     Subthreshold depolarization of soma propagates into axons for a distance and facilitates synaptic transmission. Using simulation with the model of hippocampal mossy fiber axon, we found that depolarization reduces the action potential-induced the presynaptic calcium entry, while subthreshold depolarization itself elicited small calcium entry.

     Front Cell Neurosci 2022    DOI: https://doi.org/10.3389/fncel.2022.966636

          ModelDB 2022　 #267512    https://modeldb.science/267512

Mechanisms of axonal afterdepolarization (ADP) 

     Axonal spikes are often followed by slow depolarization lasting for tens of ms. Using direct recording and simulation, we revealed that passive propagation by the capacitive discharge of the axonal membrane as well as voltage-dependent K and slow Na conductances underlie the generation of ADP. 

     eNeuro 2018a                              DOI: https://doi.org/10.1523/ENEURO.0254-18.2018

     Front Cell Neurosci 2019a     DOI: https://doi.org/10.3389/fncel.2019.00210

     Front Cell Neurosci 2019b     DOI: https://doi.org/10.3389/fncel.2019.00407

          ModelDB 2020　     #263034    https:/modeldb.science/263034

Analog modulation of axonal spike signaling

     Using direct recording from the single axon terminals of hippocampal mossy fibers, both duration and amplitude of axonal spike are subject to modulation by preceding action potential-ADP sequence, deviating from the conventional notion of digital nature of axonal spike signaling. Short-term plasticity of axonal spike also impacts on transmitter release from the axon terminals. 

      eNeuro 2018b                              DOI: https://doi.org/10.1523/ENEURO.0415-17.2018

      Front Cell Neurosci 2019b     DOI: https://doi.org/10.3389/fncel.2019.00407

　This work was press released from the Hokkaido University web page (2018/2/27).   jp

Timing of synapse delivery of AMPA-type glutamate receptors

     The hippocampal CA1 synapse displays prominent plasticity by changing the expression of postsynaptic AMPA receptors. Using photochemical inactivation of AMPA receptors by UV illumination with the photoreactive blocker ANQX, temporal dynamics of synaptic delivery of AMPA receptors from the reserve pools were explored. It was revealed that AMPA receptors were incorporated following a high-frequency stimulus for inducing plasticity.

     J Neurosci 2012      DOI: https://doi.org/10.1523/jneurosci.0720-12.2012

　This work was press released from the Hokkaido University web page (2012/5/9).   jp

                          https://www.hokudai.ac.jp/news/120509_pr_med.pdf

Amplification of presynaptic plasticity by calcium store

     Hippocampal mossy fiber synapse exerts presynaptic long-term potentiation which does not require activation of NMDA receptors. Using the optical measurement of calcium dynamics within the mossy fiber terminals, this form of plasticity has been shown to be triggered calcium release from the presynaptic calcium store. Specifically, type 2 ryanodine receptors are shown to be involved.

     PNAS 2008      DOI: https://doi.org/10.1073/pnas.0802175105

　This work was press released and reported in Asahi (2008/8/15) and Mainichi newspapers (2008/8/5).

Expression mechanisms of presynaptic plasticity

     The mechanisms underlying the presynaptic form of plasticity at the hippocampal mossy fiber synapse were investigated using optical measurement of presynaptic calcium and found that the amount of calcium entry was unchanged. Involvement of kainite-type glutamate receptors in large short-term facilitation was shown by the same optical approach.

     J Neurosci 2002a      DOI: https://doi.org/10.1523/JNEUROSCI.22-24-10524.2002

     J Neurosci 2002b      DOI: https://doi.org/10.1523/JNEUROSCI.22-21-09237.2002

Roles of presynaptic glutamate receptors

     At hippocampal mossy fiber synapses, it has been demonstrated that group II metabotropic glutamate receptors (mGluR) modulate transmitter release while kainite-type glutamate receptors regulate axonal excitability. Journal of Physiology paper in 1996 demonstrating selective block of mossy fiber transmission by the agonist of group II mGluR was cited by many papers on the hippocampal mossy fiber synapse.

     J Physiol 2000      DOI: https://doi.org/10.1111/j.1469-7793.2000.t01-1-00653.x

     J Physiol 1998      DOI: https://doi.org/10.1111/j.1469-7793.1998.833bm.x

     Prog Neurobio 1998      DOI: https://doi.org/10.1016/S0301-0082(97)00085-3

     *J Physiol 1996      DOI: https://doi.org/10.1113/jphysiol.1996.sp021395

           *This work was selected as the top 40 most influential Journal of Physiology papers from Japan and was published in the virtual issues celebrating the Physiological Society of Japan’s 100th anniversary.

Roles of residual calcium in short-term synaptic plasticity

     At many synapses, the synaptic strength was dynamically tuned by their history of activity. As a mechanism of this short-term plasticity, it has been long postulated that a build-up of the presynaptic calcium level caused enhanced transmitter release. Using the optical control of presynaptic calcium concentration by photolysis of caged compounds, the residual calcium hypothesis was successfully proved.

     Nature 1994      DOI: https://doi.org/10.1038/371603a0

Identification of presynaptic calcium channel

     Calcium entry into the presynaptic terminals is essential for transmitter release, although the subtypes of the calcium channels had not been identified in the central nervous system. Since the application of ω-conotoxin GVIA suppresses synaptic transmission in hippocampal slices, the N-type calcium channels were shown to be involved in transmitter release.

     Neurosci Lett 1988      DOI: https://doi.org/10.1016/0304-3940(88)90253-4