Jun Hee Kim, Ph.D.
Our research interest is to understand regulatory mechanisms of presynaptic excitability and synaptic transmission in the central nervous system (CNS) during physiological or pathological conditions, using electrophysiology and imaging techniques.
Synapse is the critical structure where neuronal information is transmitted from neuron to neuron. Presynaptic excitability is crucial for the reliable transmission of neuronal information in the central nervous systems. However, it is very difficult to study presynaptic excitability and vesicular glutamate release directly at the CNS nerve terminals, because the sub-micron size of CNS nerve terminals has precluded direct recordings. To study presynaptic properties directly, we take advantage of the calyx of Held, a large nerve terminal that allows direct presynaptic recordings. The calyx of Held is an excitatory glutamatergic nerve terminal of the globular bushy cells, which cross the brainstem midline and synapse onto the contra-lateral principal cells of the medial nucleus of the trapezoid body. The calyx of Held synapse is well established as a model for examining synaptic function. One can simultaneously record directly from the presynaptic terminal and the postsynaptic neuron, thereby allowing modulation presynaptic parameters such as ionic concentration and Ca2+ buffers.
Project I. Fundamental role of CNS myelination in synaptic functions in the auditory nervous system
Myelinated axons in the mammalian CNS are uniquely designed to support rapid and efficient saltatory impulse propagation. Partial or complete loss of myelin due to genetic mutations or autoimmune disease, as in the case of multiple sclerosis, can be emotionally devastating and physically debilitating. However, most studies related to demyelination have focused on the PNS and spinal cord axons, and little is known about how loss of myelin sheaths affects the synaptic transmission at the single synapse level in the mammalian central nervous system. Myelin loss in the CNS can lead to axonal death and irreversible damage to sensory function. Our research goals is to investigate the cellular mechanisms that lead to hearing disorders due to the aberrant transmission of auditory signals. We study changes in presynaptic excitability and synaptic function that result from demyelination, and to determine the cellular mechanisms of these changes at single synapses in the auditory brainstem, using patch-clamp recording and presynaptic Na+ and Ca2+ imaging in the calyx of Held synapse in the auditory brainstem. We use the Long-Evans Shaker rat, a severely demyelinating mutant that completely lacks central nervous system myelination. This study will give important information about synaptic transmission in the single CNS synapse following multiple sclerosis, as well as will enable to develop the novel therapeutic strategies for a permanent childhood hearing loss due to myelin loss.
Project II. Cellular mechanisms of neuronal injury during hypoxia-ischemia
Brain ischemia arising because of stroke, cardiac arrest, near drowning, or open-heart surgery result in severe neurological disabilities, either temporary or permanent. In particular, ischemic neuronal injury in the fetal and newborn brain can result in severe long-term disorders such as cerebral palsy, mental retardation and seizures. During brain ischemia (lack of energy in nervous tissues due to a lack of oxygen and glucose, the main fuel for the brain), an excessive rise in glutamate causes neurodegeneration of axons and nerve terminals as well as postsynaptic neurons. However, studies of ischemic injury have focused primarily on postsynaptic excitotoxicity. The basic biological mechanisms in a nerve terminal that lead to neuronal damage and death during ischemia are still poorly understood, because the sub-micron size of CNS nerve terminals has precluded direct recordings. The long-term goal of this research is to investigate fundamental mechanisms of glutamate release and pathological processes at the central synapses. We study the effects of ischemia on single axons and synapses in developing brain by studying the electrophysiological properties of a single axon and its nerve terminal in the mammalian central nervous system. As a result of this study, we will identify an important glutamate release process that is only active during ischemia, and it could be possible to prevent glutamate release only during ischemia.
Project III. Cellular mechanisms of auditory processing disorder in premature newborn
Prematurity is one of the leading causes of perinatal mortality and long-term disability. About 22% of extremely premature children suffer from intellectual, cognitive, academic, and language difficulties. Extremely premature children suffer from intellectual, cognitive, academic, and language difficulties. Poor reading-speaking abilities and memory in premature children are associated with an auditory processing disorder. Fetal auditory development is essential for early brain maturation and health neuronal circuitry in the developing brain. Our long-term goal is investigate the cellular mechanisms that lead to impaired sensory system and neural circuitry in the developing brain of the premature infant. The outcome of this study will have a significant impact on our understanding of auditory processing in the premature infant, an important initial step towards preventive treatment to improve hearing disorders and language difficulties in premature children.
Emmanuelle Berret, Tara Barron, Jie Xu, Emily Debner, Eun Jung Kim & Jun Hee Kim. Oligodendroglial excitability mediated by glutamatergic inputs and Nav1.2 activation. Nature Communications 8, Article number: 557 (2017) doi:10.1038/s41467-017-00688-0
Berret E, Kim SE, Lee SY, Kushmerick C and Kim JH (2016). Functional and structural properties of ion channels at the nerve terminal depends on compact myelin. J Physiol., 594 (19): 5593-5609.
Xu J, Berret E, and Kim JH (2016). Activity-dependent formation and location of Nav channel cluster at the CNS nerve terminal. J Neurophysiol. DOI: 10.1152/jn.00617.