Our research is aimed at elucidating how ion channels regulate the processing of information by neurons in the cerebral cortex, i.e., the diverse mechanisms neurons use to convert synaptic input into action potentials. The proposed experiments will determine basic principles of how voltage-gated potassium (Kv) channels regulate postsynaptic processing of inputs in layer 5 (L5) neocortical pyramidal neurons (PNs). PNs are the output cells of cortex and key players in learning, memory, and sensorimotor processing, as well as the targets of central nervous system diseases (e.g., epilepsy). The proposed studies go beyond the standard notion that potassium channels act as an intrinsic brake on excitability. They are designed to determine the influence Kv2 and Kv7 channels have on the types of information that L5 PNs respond to and how that information is filtered before downstream transmission. We will study mechanisms controlling firing behavior in two classes of pyramidal neurons: intratelencephalic-projecting (IT) and pyramidal tract (PT) type, represented by two genetically-identified PNs with GFP expressed in populations of L5 PNs under control of unique genes: etv1 (IT) and thy1 (PT). We will test hypotheses concerning how Kv2 and Kv7 channels regulate burst firing (Aim 1) and continuous firing (repetitive bursting and suprathreshold resonance:
Aim 2). Kv channel properties and expression are dynamic. They can undergo plastic changes in response to activity or signaling pathways and thus change neuronal filtering properties. Thus, we will also study use-dependent plasticity of intrinsic excitability (Aim 3). We use transgenic mouse lines and state-of-the-art electrophysiological approaches, including somatic / dendritic paired recordings, dynamic clamp, internal pipet perfusion, nucleated patch and on-cell patch recordings, as well as whole cell and gramicidin perforated patch. We also use two-photon and charge-coupled device (CCD)-based Ca2+ imaging systems. Our stimulus protocols are designed to mimic natural synaptic activity arriving at the soma of a neuron (the common summing point for all dendrites) and will be systematically varied to simulate different levels or composition of inputs. Our findings will have major implications for cortical processing, ion channel function, understanding neural computations, and mechanisms underlying epilepsy, anesthesia, learning and memory.

Public Health Relevance

Our research is focused on determining how ion channels regulate the ability of neocortical pyramidal neurons to process information, in particular the transformation of synaptic inputs into trains of action potentials. These cells are essential elements of learning, memory and sensorimotor processing, as well as the targets of central nervous system diseases (e g, epilepsy). Our findings will have major implications for cortical processing, ion channel function, understanding neural computations, and mechanisms underlying epilepsy, anesthesia, and learning and memory.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Silberberg, Shai D
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University of Tennessee Health Science Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Wang, Lie; Chandaka, Giri Kumar; Foehring, Robert C et al. (2018) Changes in potassium channel modulation may underlie afterhyperpolarization plasticity in oxytocin neurons during late pregnancy. J Neurophysiol 119:1745-1752
Baker, Arielle; Kalmbach, Brian; Morishima, Mieko et al. (2018) Specialized Subpopulations of Deep-Layer Pyramidal Neurons in the Neocortex: Bridging Cellular Properties to Functional Consequences. J Neurosci 38:5441-5455
Guan, Dongxu; Pathak, Dhruba; Foehring, Robert C (2018) Functional roles of Kv1-mediated currents in genetically identified subtypes of pyramidal neurons in layer 5 of mouse somatosensory cortex. J Neurophysiol 120:394-408
Kirchner, Matthew K; Foehring, Robert C; Callaway, Joseph et al. (2018) Specificity in the interaction of high-voltage-activated Ca2+ channel types with Ca2+-dependent afterhyperpolarizations in magnocellular supraoptic neurons. J Neurophysiol 120:1728-1739
Kirchner, Matthew K; Foehring, Robert C; Wang, Lie et al. (2017) Phosphatidylinositol 4,5-bisphosphate (PIP2 ) modulates afterhyperpolarizations in oxytocin neurons of the supraoptic nucleus. J Physiol 595:4927-4946
Pathak, Dhruba; Guan, Dongxu; Foehring, Robert C (2016) Roles of specific Kv channel types in repolarization of the action potential in genetically identified subclasses of pyramidal neurons in mouse neocortex. J Neurophysiol 115:2317-29
Guan, Dongxu; Armstrong, William E; Foehring, Robert C (2015) Electrophysiological properties of genetically identified subtypes of layer 5 neocortical pyramidal neurons: Ca²? dependence and differential modulation by norepinephrine. J Neurophysiol 113:2014-32
Bishop, Hannah I; Guan, Dongxu; Bocksteins, Elke et al. (2015) Distinct Cell- and Layer-Specific Expression Patterns and Independent Regulation of Kv2 Channel Subtypes in Cortical Pyramidal Neurons. J Neurosci 35:14922-42
Guan, Dongxu; Armstrong, William E; Foehring, Robert C (2013) Kv2 channels regulate firing rate in pyramidal neurons from rat sensorimotor cortex. J Physiol 591:4807-25
Andrade, Rodrigo; Foehring, Robert C; Tzingounis, Anastasios V (2012) The calcium-activated slow AHP: cutting through the Gordian knot. Front Cell Neurosci 6:47

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