Dax Aaron Hoffman, Ph.D.
Section on Molecular Neurophysiology and Biophysics
The central nervous system underlies all our experiences, actions, emotions, knowledge, and memories. With billions of neurons each firing hundreds of times per second, the complexity of the brain is stunning. To pare down the task of understanding something so complex, our research approach calls for studying the workings of a single central neuron—the pyramidal neuron from the CA1 region of the hippocampus. The hippocampus is essential for long-term memory in humans and is among the first brain regions affected by epilepsy and Alzheimer’s disease. To understand how the hippocampus stores and processes information, we focus on one of its principal cell types, the CA1 pyramidal neuron. Each pyramidal neuron in the CA1 region of the hippocampus receives tens of thousands of inputs onto its dendrites, and it is commonly thought that information is stored by altering the strength of individual synapses (synaptic plasticity). Recent evidence suggests that the regulation of synaptic surface expression of glutamate receptors can, in part, determine synaptic strength. However, the dendrites contain an abundance of ion channels that are involved in receiving, transforming, and relaying information in the dendrites, adding an additional layer of complexity to neuronal information processing.
We have found that the A-type potassium channel subunit Kv4.2 is highly expressed in the dendritic regions of CA1 neurons in the hippocampus and, as one of the primary regulators of dendritic excitability, plays a pivotal role in information processing. Kv4.2 is targeted for modulation during the types of plasticity thought to underlie learning and memory. Moreover, the functional expression level of Kv4.2 was found to regulate the subtype expression of the NMDA–type glutamate receptors, the predominate molecular devices controlling synaptic plasticity and memory. We are currently following up on these findings with more detailed investigations into the mechanisms of activity-dependent Kv4.2 regulation. In addition, we have begun investigating the role of dendritic voltage-gated channels in CNS disorders, including autism-spectrum disorder and Alzheimer’s disease, that exhibit profound changes in neuronal excitability along with learning and memory deficits.
Dr. Dax Hoffman received his B.S. in Genetics from the University of Minnesota in 1994 and his Ph.D. from Baylor College of Medicine in 1999, where he studied dendritic K+ channels with Dr. Dan Johnston. During a postdoctoral fellowship with Dr. 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.
Gray EE, Murphy JG, Liu Y, Trang I, Tabor GT, Lin L, Hoffman DA. Disruption of GpI mGluR-Dependent Cav2.3 Translation in a Mouse Model of Fragile X Syndrome. J Neurosci. 2019;39(38):7453-7464.
Lin L, Petralia RS, Lake R, Wang YX, Hoffman DA. A novel structure associated with aging is augmented in the DPP6-KO mouse brain. Acta Neuropathol Commun. 2020;8(1):197.
Hu JH, Malloy C, Hoffman DA. P38 Regulates Kainic Acid-Induced Seizure and Neuronal Firing via Kv4.2 Phosphorylation. Int J Mol Sci. 2020;21(16).
Hu JH, Malloy C, Tabor GT, Gutzmann JJ, Liu Y, Abebe D, Karlsson RM, Durell S, Cameron HA, Hoffman DA. Activity-dependent isomerization of Kv4.2 by Pin1 regulates cognitive flexibility. Nat Commun. 2020;11(1):1567.
Bellotti A, Murphy J, Lin L, Petralia R, Wang YX, Hoffman D, O'Leary T. Paradoxical relationships between active transport and global protein distributions in neurons. Biophys J. 2021;120(11):2085-2101.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on September 2nd, 2021