Education

1972  University of Zurich; M.S. Molecular Biology
1977  University of Zurich; M.S. Molecular Biology

Biosketch                Top

Ph.D. in molecular biology (molecular virology) from the University of Zurich, Switzerland. Postdoctoral fellow at Stanford University, California (work in molecular immunology).

Research Overview                  Top

The fast processing and transmission of signals in the nervous system are required to produce rapid behavioral responses to environmental changes. Fast spiking has garnered increasing attention from behavioral and cognitive neuroscientists in recent years because fast neuronal firing has been implicated in motor function, auditory signal processing, attention, and even awareness itself. To attain fast spike frequencies, neurons must constrain the action-potential duration and the ensuing refractory period, while still allowing for sufficient recovery of sodium channels from inactivation for renewed action-potential generation.

Kv3-type voltage-gated potassium (Kv) channels are uniquely suited to play these roles by virtue of their ability to open and close with exceptional speed. There are four types of Kv3 channels, Kv3.1-Kv3.4, often expressed in neurons capable of firing at very high rates either tonically or within bursts. These neurons are located in areas known to be involved in a variety of behavioral functions, ranging from sensory to motor to cognitive. Indeed, our laboratory has shown that the elimination of Kv3 genes leads to a variety of physiological and behavioral phenotypes. Loss of Kv3.1 results in hyperactivity and dramatically reduced sleep; in contrast, Kv3.3 ablation leads to motor dysfunction resembling the pathological phenotype of recently discovered natural mutations in the human Kv3.3 gene causing a form of spinocerebellar ataxia. The combined loss of Kv3.1 and Kv3.3 elicits marked tremor, myoclonus and severe ataxia, as well as extreme alcohol sensitivity.

It is likely that the behavioral changes are directly caused by the altered electrical properties of neurons that lack Kv3.1 or Kv3.3 channels. To understand how the changes in electroresponsiveness of distinct neuronal populations in the brain results in the observed behavioral alterations, we selectively re-express in Kv3-deficient mice the missing Kv3.1 and Kv3.3 channels in different subsets of neurons that normally express these channels in wild-type mice. As a complementary strategy, we also selectively suppress Kv3 channel activity in wild-type mice by targeted expression of dominant-negative Kv3 subunits in different neuronal populations to interfere with normal Kv3 channel activity. Cell-specific expression and suppression of Kv3 function is achieved using either neuron-specific promoters or, where specific promoters are not available, recombinant adeno-associated virus encoding Kv3 channel subunits. The strategy of neuron-specific Kv3 re-expression or suppression followed by behavioral tests and by the subsequent electrophysiological characterization of neurons in brain slices enables us to correlate distinct behavioral changes with the corresponding electrical alterations in neuronal subpopulations. Hence, our work identifies the actual brain loci that are responsible for altered behavior in Kv3-null mutant mice and helps us understand how the loss of Kv3 channels produces behavioral deficits.

Research Interests

Molecular neuroscience; biophysics of ion channels; molecular and cellular basis of normal and pathological behavior

Recent Publications            Top  

Primary Research Articles

Porcello, D.M., Ho, C.S., Joho, R.H. and Huguenard, J.R.  Resilient RTN fast spiking in Kv3.1 null mice suggests redundancy in the action potential repolarization mechanism. J. Neurophysiol. 87: 1303-1310 (2002).

Metzger, F., Repunte-Canonigo, V., Matsushita, S., Akemann, W., Diez-Garcia, J., Ho, C.S., Iwasato, T., Grandes, P., Itohara, S., Joho, R.H. and Knöpfel, T.  Transgenic mice expressing a pH and C1¯ sensing yellow-fluorescent protein under the control of a potassium channel promoter.  Europ.J.Neurosci.  15: 40-50 (2002).

 Espinosa, F., McMahon, A., Chan, E., Wang, S., Ho, C.S., Heintz, N. and Joho, R.H. Alcohol hypersensitivity, increased locomotion and spontaneous myoclonus in mice lacking the potassium channels Kv3.1 and Kv3.3. J. Neurosci. 6657-6665 ( 2001).

Espinosa, F., Fleischhauer, R., McMahon, A. and Joho, R.H. Dynamic interaction of S5 and S6 during voltage-controlled gating in a potassium channel. J. Gen. Physiol. 118:157-169 (2001).

Sánchez, J.A., Ho, C.S., Vaughan, D.M., Garcia, M.C., Grange, R.W. and Joho, R.H. Muscle and motor-skill dysfunction in a K⁺ channel-deficient mouse are not due to altered muscle excitability or fiber type but depend on the genetic background. Pflügers Arch. 440:34-41 (2000).

Fleischhauer, R., Davis, M.W., Dzhura, I., Neely, A., Avery, L. and Joho, R.H. Ultrafast inactivation causes inward rectification in a voltage-gated K⁺ channel from Caenorhabditis elegans. J. Neurosci. 20:511-520 (2000).

Davis, M.W., Fleischhauer, R., Dent, J.A., Joho, R.H. and Avery, L. A mutation in the C. elegans EXP-2 potassium channel that alters feeding behavior. Science 286:2501-2504 (1999).

Joho, R.H., Ho, C.S. and Marks, G.A. Increased g-and decreased d-oscillations in a mouse deficient for a potassium channel expressed in fast-spiking neurons. J. Neurophysiol. 82:1855-1864 (1999).

Liu, Y. and Joho, R.H. A side chain in S6 influences both open-state stability and ion permeation in a voltage-gated K⁺ channel. Pflügers Arch. 435:654-661 (1998).

Joho, R.H., Ho, C.S., Armitage, R. and Marks, G. Physiological and behavioral alterations in a mutant mouse deficient for the voltage-gated K⁺ channel Kv3.1. Pflügers Arch. 434:R90-R91 (1997).

Verma, S., Border, B. and Joho, R.H. Regional and cellular expression pattern of four K⁺ channel mRNAs in the adult rat brain. Molecular Brain Research 46:54-62 (1997).

Ho, C.S., Grange, R.W. and Joho, R.H. Pleiotropic effects of a disrupted K⁺ channel gene: Reduced body weight, impaired motor skill and muscle contraction, but no seizures. Proc. Natl. Acad. Sci. U.S.A. 94:1533-1538 (1997).

Current Lab Staff                 Top

Rooms NB4.102
Telephone: 214-648-18xx

Research Fellows

Postdoctoral Fellows

Technicians