Neuroscience@NIH > Faculty

Senior Investigator

Dax Hoffman, Ph.D.

Porter Neuroscience Research Center
Building 35 Room 3C-905

35 Convent Drive MSC 4995
Bethesda MD 20892-4995

Office: (301) 402-6772
Lab: (301) 402-6772
Fax: (301) 402-4777
hoffmand@mail.nih.gov

Dr. Hoffman received his B.S. in Genetics from the University of Minnesota in 1994 and his Ph.D. from Baylor College of Medicine 1999, where he studied dendritic K+ channels with Dr. Dan Johnston. During a postdoctoral fellowship with Bert Sakmann at the Max Planck Institute for Medical Research in Heidelberg Germany, he investigated synaptic plasticity and Ca2+ signaling in transgenic and gene-targeted mice. Dr. Hoffman became head of the Molecular Neurophysiology and Biophysics Unit, NICHD in 2002. His laboratory explores dendritic signal processing in CA1 pyramidal neurons of the hippocampus.

	The dendrites of CA1 pyramidal neurons receive and process tens of thousands of excitatory and inhibitory inputs in ways that are not well understood. The presence of voltage-gated channels (active dendrites) suggests that computations are performed in dendrites, subsequent to synaptic input. Although much current and past research on synaptic plasticity in CA1 pyramidal neurons has focused on glutamate receptor regulation, relatively little is known about how voltage-gated channels influence synaptic integration. The Hoffman group combines molecular, biochemical and electrophysiological approaches to investigate the roles of dendritic voltage-gated channels in regulating neuronal development and synaptic plasticity in the mammalian hippocampus. To achieve this, the lab comprises an interdisciplinary team with expertise in cellular and molecular biology, biochemistry, electrophysiology, fluorescence imaging and computer modeling. These approaches allow us to assay channel function and regulation at the molecular scale in living cells. At the larger scale, we are investigating how mutations or mis-regulation of ion channel function, trafficking or localization negatively affects neuronal function and development. Mouse models are employed to assay the effect of these dysfunctions on learning and memory and in pathophysiological processes thought to have a synaptic basis, including Autism, Fragile X Syndrome and Alzheimer's disease. Much of our work has focussed on the somatodendritic voltage-gated potassium channel subunit, Kv4.2. Kv4.2 is highly expressed in CA1 dendrites and is the molecular identity of the subthreshold, rapidly inactivating (A-type) potassium current that has been shown to influence CA1 dendritic signal propagation. The large density of dendritic Kv4.2 channels acts to shape incoming synaptic signals and limit action potential backpropagation into dendrites. We have found that dendritic Kv4.2 surface expression is regulated in an activity-dependent manner, providing a new means by which Kv4.2 channels may influence synaptic function.

The dendrites of CA1 pyramidal neurons receive and process tens of thousands of excitatory and inhibitory inputs in ways that are not well understood. The presence of voltage-gated channels (active dendrites) suggests that computations are performed in dendrites, subsequent to synaptic input. Although much current and past research on synaptic plasticity in CA1 pyramidal neurons has focused on glutamate receptor regulation, relatively little is known about how voltage-gated channels influence synaptic integration. The Hoffman group combines molecular, biochemical and electrophysiological approaches to investigate the roles of dendritic voltage-gated channels in regulating neuronal development and synaptic plasticity in the mammalian hippocampus. To achieve this, the lab comprises an interdisciplinary team with expertise in cellular and molecular biology, biochemistry, electrophysiology, fluorescence imaging and computer modeling. These approaches allow us to assay channel function and regulation at the molecular scale in living cells. At the larger scale, we are investigating how mutations or mis-regulation of ion channel function, trafficking or localization negatively affects neuronal function and development. Mouse models are employed to assay the effect of these dysfunctions on learning and memory and in pathophysiological processes thought to have a synaptic basis, including Autism, Fragile X Syndrome and Alzheimer's disease.

Much of our work has focussed on the somatodendritic voltage-gated potassium channel subunit, Kv4.2. Kv4.2 is highly expressed in CA1 dendrites and is the molecular identity of the subthreshold, rapidly inactivating (A-type) potassium current that has been shown to influence CA1 dendritic signal propagation. The large density of dendritic Kv4.2 channels acts to shape incoming synaptic signals and limit action potential backpropagation into dendrites. We have found that dendritic Kv4.2 surface expression is regulated in an activity-dependent manner, providing a new means by which Kv4.2 channels may influence synaptic function.

Activity-Dependent Trafficking of Kv4.2


Time-lapse images showing Kv4.2g fluorescent intensity decrease upon AMPA (50 uM) stimulation in spines of hippocampal neurons co-expressing Kv4.2g and tdTomato.

Emilie Campanac, Ph.D.
Visiting Fellow
Ashley Charest, B.S.
Postbaccalaureate IRTA
Erin Gray, Ph.D.
Postdoctoral Fellow
Jakob Gutzmann, Ph.D.
Visiting Fellow
Jiahua Hu, Ph.D.
Staff Scientist
Lin Lin, Ph.D.
Research Fellow
Ying Liu, M.D.
Biologist
Jon Murphy, Ph.D.
Postdoctoral Fellow
Jung Park, B.S.
Post baccalaureate Fellow
Ivan Trang, B.S.
Postbaccalaureate IRTA

1) Hall AM, Throesch BT, Buckingham SC, Markwardt SJ, Peng Y, Wang Q, Hoffman DA, Roberson ED (2015)

Tau-dependent kv4.2 depletion and dendritic hyperexcitability in a mouse model of Alzheimer's disease
J Neurosci, 35(15):6221-30. , doi: 10.1523/JNEUROSCI.2552-14.2015

2) Lin L, Long LK, Hatch MM, Hoffman DA (2014)

DPP6 Domains Responsible for its Localization and Function
J Biol Chem, 289(46):32153-65. , doi: 10.1074/jbc.M114.578070. Epub 2014 Sep 4

3) Campanac E, Hoffman DA. (2013)

Repeated Cocaine Exposure Increases Fast-Spiking Interneuron Excitability in the Rat Medial Prefrontal Cortex.
J Neurophysiol, 109(11), 2781-92

4) Lin L, Sun W, Throesch B, Kung F, Decoster JT, Berner CJ, Cheney RE, Rudy B and Hoffman DA (2013)

DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development
Nature Commun, 4, 2270

5) Bukalo O, Campanac E, Hoffman DA, Fields RD. (2013)

Synaptic plasticity by antidromic firing during hippocampal network oscillations.
Proc Natl Acad Sci U S A, 110(3), 5175-80

6) Kiselycznyk C, Hoffman DA, Holmes A. (2012)

Effects of genetic deletion of the Kv4.2 voltage-gated potassium channel on murine anxiety-, fear- and stress-related behaviors.
Biol Mood Anxiety Disord., 2(1), 5

7) Murase S, Kim E, Lin L, Hoffman DA, McKay RD. (2012)

Loss of signal transducer and activator of transcription 3 (STAT3) signaling during elevated activity causes vulnerability in hippocampal neurons.
J Neurosci., 32(44), 15511-20

8) Nestor MW, Hoffman DA. (2012)

Aberrant dendritic excitability: a common pathophysiology in CNS disorders affecting memory?
Mol Neurobiol, 45(3), 478-87

9) Kim E, Hoffman DA. (2012)

Dynamic regulation of synaptic maturation state by voltage-gated A-type K+ channels in CA1 hippocampal pyramidal neurons.
J Neurosci., 10;32(41), 14427-32

10) Wei Sun, Jon K. Maffie, Lin Lin, Ronald S. Petralia, Bernardo Rudy and Dax A. Hoffman (2011)

DPP6 establishes the A-type K+ current gradient critical for the regulation of dendritic excitability in CA1 hippocampal neurons
Neuron, 71(6), 1102-15

11) Lin L, Sun W, Kung F, DellAcqua ML and Hoffman DA (2011)

AKAP79/150 impacts intrinsic excitability of hippocampal neurons through phospho-regulation of A-type K+ channel trafficking
J. Neuroscience, 26;31(4), 1323-32

12) Nestor M, Hoffman DA (2011)

Differential cycling rates of Kv4.2 channels in proximal and distal dendrites of hippocampal CA1 pyramidal neurons
Hippocampus

13) Jung SC, Eun SY, Kim J, Hoffman DA. (2011)

Kv4.2 block of long-term potentiation is partially dependent on synaptic NMDA receptor remodeling.
Brain Res Bull. , 15;84(1), 17-21

14) Shah MM, Hammond RS, Hoffman DA. (2010)

Dendritic ion channel trafficking and plasticity.
Trends Neurosci

15) Lin L, Sun W, Wikenheiser AM, Kung F, Hoffman DA. (2010)

KChIP4a regulates Kv4.2 channel trafficking through PKA phosphorylation.
Mol Cell Neurosci., 43(3), 315-25

16) Jung S-C, Kim J, and Hoffman, DA (2008)

Rapid, bidirectional remodeling of synaptic NMDA receptor subunit composition by A-type K+ channel activity in hippocampal CA1 pyramidal neurons
Neuron, 60(4), 657-71

17) Kim J, Jung SC, Clemens AM, Petralia RS, Hoffman DA. (2007)

Regulation of Dendritic Excitability by Activity-Dependent Trafficking of the A-Type K+ Channel subunit Kv4.2.
Neuron, 54(6), 933-47

18) Kwon OB, Longart M, Vullhorst D, Hoffman DA, Buonanno A. (2005)

Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses.
J. Neurosci., 12;25(41), 9378-83

19) Kim J, Wei DS, Hoffman DA (2005)

Kv4 potassium channel subunits control action potential repolarization and frequency dependent broadening in rat hippocampal CA1 pyramidal neurons.
J. Phys., 569, 41-57

20) Migliore M, Hoffman DA, Magee JC, Johnston D. (1999)

Role of an A-type K+ conductance in the back-propagation of action potentials in the dendrites of hippocampal pyramidal neurons.
J Comput Neurosci., 7(1), 5-15

21) Hoffman DA, Johnston D. (1999)

Neuromodulation of dendritic action potentials.
J Neurophysiol, 81(1), 408-11

22) Hoffman DA, Johnston D. (1998)

Downregulation of transient K+ channels in dendrites of hippocampal CA1 pyramidal neurons by activation of PKA and PKC.
J Neurosci , 18(10), 3521-8

23) Hoffman, D.A., Magee, J., Colbert, C. & Johnston, D. (1997)

K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons
Nature, 387, 869-875

24) Colbert CM, Magee JC, Hoffman DA, Johnston D. (1997)

Slow recovery from inactivation of Na+ channels underlies the activity-dependent attenuation of dendritic action potentials in hippocampal CA1 pyramidal neurons.
J. Neurosci., 17(17), 6512-21.

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