Browsing by Author "Govindaraju, Aravind Chenrayan"

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    Computational Model of Synaptic Transmission at the Vestibular Hair Cell Calyx Synapse
    (2020-08-13) Govindaraju, Aravind Chenrayan; Raphael, Robert M
    "In the sensory neuroepithelia of the vestibular system, the organ which detects head orientation and acceleration, Type I sensory hair cells are enveloped by a cup-like process (calyx) of the afferent neuron and possess a characteristic low voltage activated potassium conductance (gKL) on their basolateral surface. The presence of the calyx creates a unique synapse morphology which is thought to limit the diffusion of ions and support two modes of neurotransmission between the hair cell and afferent neuron: Quantal (Q) – through the release of neurotransmitters and Non-Quantal (NQ) – through non-neurotransmitter mediated effects such as ephaptic coupling and potassium accumulation in the synaptic cleft. The importance and necessity of NQ transmission has been unclear. Direct experimental measurement of electric potentials and ion concentrations in the hair cell and afferent, let alone the synaptic cleft, is difficult. We have developed a computational model to probe the dynamic behavior of the Vestibular Hair Cell Calyx (VHCC) synapse and understand the role of non-quantal transmission. The VHCC model uses expressions for K+ and Na+ electro-diffusion in the cleft, Hodgkin-Huxley-like ion currents based on whole-cell recordings, stochastic vesicle release, and the cable equation to calculate potentials in the hair cell, cleft, afferent calyx and afferent fiber. Model simulations suggest that ephaptic coupling at the VHCC synapse is active at all frequencies, does not exhibit high-pass behavior as previously thought and may be an indefatigable method of communication between the type I hair cell and calyx."
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    Nonquantal transmission at the vestibular hair cell–calyx synapse: KLV currents modulate fast electrical and slow K+ potentials
    (PNAS, 2023) Govindaraju, Aravind Chenrayan; Quraishi, Imran H.; Lysakowski, Anna; Eatock, Ruth Anne; Raphael, Robert M.
    Vestibular hair cells transmit information about head position and motion across synapses to primary afferent neurons. At some of these synapses, the afferent neuron envelopes the hair cell, forming an enlarged synaptic terminal called a calyx. The vestibular hair cell–calyx synapse supports a mysterious form of electrical transmission that does not involve gap junctions, termed nonquantal transmission (NQT). The NQT mechanism is thought to involve the flow of ions from the presynaptic hair cell to the postsynaptic calyx through low-voltage-activated channels driven by changes in cleft [K+] as K+ exits the hair cell. However, this hypothesis has not been tested with a quantitative model and the possible role of an electrical potential in the cleft has remained speculative. Here, we present a computational model that captures experimental observations of NQT and identifies features that support the existence of an electrical potential (ϕ) in the synaptic cleft. We show that changes in cleft ϕ reduce transmission latency and illustrate the relative contributions of both cleft [K+] and ϕ to the gain and phase of NQT. We further demonstrate that the magnitude and speed of NQT depend on calyx morphology and that increasing calyx height reduces action potential latency in the calyx afferent. These predictions are consistent with the idea that the calyx evolved to enhance NQT and speed up vestibular signals that drive neural circuits controlling gaze, balance, and orientation.
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    The Vestibular Hair Cell-Calyx Model: Insights into ion channels, experimental data, and ephaptic transmission in the vestibular epithelium
    (2023-04-21) Govindaraju, Aravind Chenrayan; Raphael, Robert M
    A system of bony canals and membranous ducts in the inner ear, collectively called the vestibular system, contains sensory cells that rapidly transduce head motion. Information from these cells drives some of the fastest reflexes in the body such as the vestibulo-ocular reflex and vestibulo-collic reflex which are vital for maintaining gaze, balance and orientation. Of these cells, the Type I sensory hair cells are surrounded by a cup-like terminal (calyx) of the afferent neuron and possess a characteristic low voltage activated potassium conductance (gKL) on their basolateral surface. The apposition of the presynaptic hair cell membrane and the postsynaptic calyx creates a unique synapse morphology that limits the diffusion of ions entering the intermediate cleft space. Transmission between the hair cell and afferent neuron across this cleft space occurs through the release of neurotransmitters (quantal) or without conventional neurotransmitters (nonquantal). I developed a computational model of the Vestibular Hair Cell-Calyx (VHCC) to investigate the mechanism of nonquantal transmission. The VHCC model uses expressions for K+ and Na+ electrodiffusion in the cleft, Hodgkin-Huxley-like ion currents based on whole-cell recordings, and the cable equation to calculate potentials in the hair cell, cleft, afferent calyx and afferent fiber. Using the VHCC model I show that nonquantal transmission occurs through changes in cleft electrical and K+ potential and that it is a case of ephaptic (due to proximity) transmission. I have identified features in existing experimental data that support the idea of ephaptic transmission between the hair cell and afferent calyx: 1) phase of synaptic transmission, 2) retrograde transmission, 3) fast post synaptic currents. Based upon this work, I advance the hypothesis that electrical and K+ potentials change throughout the intercellular spaces of the tightly packed vestibular epithelium, not just within the VHCC synaptic cleft. If true, this may explain the speed with which vestibular afferents encode even small head motions.