The fast processing and transmission of signals in the nervous system is required to produce rapid behavioral responses to environmental changes. Fast spiking, i.e., neuronal firing at high frequency, 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 brain 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 result 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
Espinosa, F., Torres-Vega, M.A., Marks, G.A. and Joho, R.H., "Ablation of Kv3.1 and Kv3.3 potassium channels disrupts thalamocortical oscillations in vitro and in vivo." Journal of Neuroscience, 28:5570-5581, 2008
Hurlock, E.C., McMahon, A. and Joho, R.H., "Purkinje cell-restricted restoration of Kv3.3 function restores complex spikes and rescues motor coordination in Kcnc3 mutants." Journal of Neuroscience, 28:4640-4648, 2008
Joho, R.H., Marks, G.A. and Espinosa, F., "Kv3 potassium channels control the duration of different arousal states by distinct stochastic and clock-like mechanisms." European Journal of Neuroscience, 23:1567-1574, 2006
Joho, R.H., Street, C., Matsushita, S. and Knopfel, T., "Behavioral motor dysfunction in Kv3-type potassium channel-deficient mice." Genes, Brain and Behavior, 5:472-482, 2006
McMahon, A., Fowler, S.C., Perney, T.M., Akemann, W., Knopfel, T. and Joho, R.H., "Altered olivocerebellar circuit properties in the absence of the voltage-gated potassium channels Kv3.1 and Kv3.3." European Journal of Neuroscience, 19:3317-3327, 2004
SIGNIFICANT PUBLICATIONS
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." Journal of Neuroscience, 21:6657-6665, 2001
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
Hartmann, H.A., Kirsch, G.E., Drewe, J.A., Taglialatela, M., Joho, R.H. and Brown, A.M., "Exchange of conduction pathways between two related potassium channels." Science, 251:942-944, 1991
Frech, G.C., VanDongen, A.M.J., Schuster, G., Brown, A.M. and Joho, R.H., "A novel potassium channel with delayed rectifier properties isolated from rat brain by expression cloning." Nature, 340:642-645, 1989
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