 |
|
 |
Long-lasting changes in neural activity
A key problem in neurobiology is to understand how the properties of neurons become modified so as to produce prolonged changes in the behavior of an animal or human. In the systems that have been investigated so far, such changes have been found to be associated with long-lasting alterations in the intrinsic electrical properties of the neurons that control that behavior. To understand the mechanisms of prolonged changes in neuronal excitability, our lab has isolated the genes for many ion channels that determine the particular way that a neuron responds to its synaptic inputs. We have investigated the regulation of the ion channel proteins by second messenger pathways linked to protein kinases, which is a common mechanism for altering excitability over the time course of minutes to hours. We have also measured the way that the genes for the channels are controlled so as to influence neuronal excitability over periods of many hours or days. The systems of neurons that we have used to investigate these questions include neurons in the auditory brainstem, where the properties of potassium ion channels determine the way that a neuron responds to a sound stimulus, and a group of neurons in the abdominal ganglion of Aplysia, where brief stimulation (1-5 seconds) leads to a very prolonged changes in excitability and in the behavior of the animal. The major techniques in use include biochemical characterization of events triggered by synaptic stimulation of the neurons, cloning of ion channels, and electrical measurement of responses to intracellular microinjection of specific enzymes.
Figure caption:
1) Pseudocolor images demonstrating that application of a physiological changes in the level of a sound applied to one ear produces large changes in the level of phosphorylation of the Kv3.1b potassium channel subunit in neuron of two auditory nuclei (MNTB, medial nucleus of the trapezoid body, and AVCN, anteroventral cochlear nucleus; from Song et al., 2005). 2) Changes in the distribution of ion channels and secretory granules in response to elevations of second messengers in the terminals of neuropeptide-secreting neurons.
Selected recent publications:
Wang, L.Y. and Kaczmarek, L.K., High frequency firing helps replenish the readily releasable pool of synaptic vesicles, Nature, 398:384-388, 1998.
Jonas, E.A., Buchanan, J. and Kaczmarek, L.K., Prolonged activation of mitochondrial conductances during synaptic transmission, Science, 286:1347-1350, 1999.
Joiner WJ, Khanna R, Schlichter LC, Kaczmarek LK. Calmodulin regulates assembly and trafficking of SK4/IK1 Ca2+-activated K+ channels. J Biol Chem. 2001 Aug 8 [epub ahead of print]
Li W, Kaczmarek LK, Perney TM. Localization of two high-threshold potassium channel subunits in the rat central auditory system. J Comp Neurol. 2001 Aug 20;437(2):196-218.
McKay SE, Hislop J, Scott D, Bulloch AG, Kaczmarek LK, Carew TJ, Sossin WS. Aplysia ror forms clusters on the surface of identified neuroendocrine cells. Mol Cell Neurosci. 2001 May;17(5):821-41.
Macica CM, Kaczmarek LK. Casein kinase 2 determines the voltage dependence of the Kv3.1 channel in auditory neurons and transfected cells. J Neurosci. 2001 Feb 15;21(4):1160-8.
Macica, C.M., von Hehn, C. A.A, Wang, L.-Y., Ho C.-S., Yokoyama, S., Joho, R.H., and Kaczmarek, L.K. Modulation of the Kv3.1b potassium channel isoform adjusts the fidelity of the firing pattern of auditory neurons, J. Neurosci., 23:1133-1141, 2003.
Jonas, E.A, Hickman, J.A., Chachar, M., Polster, B.M., Brandt, T.A., Fannjiang, Y., Ivanovska, I., Basanez, G., Zimmerberg, J., Kinnally, K.W., Hardwick, J.M., and Kaczmarek, L.K. Pro-apoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals, Proc. Nat. Acad. Sci. USA, 101, 13590-13595, 2004.
Yuan, A., Santi, C.M., Wei, A., Wang, Z.-W., Pollak, K., Nonet, M., Kaczmarek, L., Crowder, C.M. and Salkoff, L. The sodium-activated potassium channel is encoded by a member of the Slo gene family, Neuron 37: 765-773, 2003.
Bhattacharjee, A. and Kaczmarek, L.K., For potassium channels, sodium is the new potassium, Trends Neurosci., 28: 422-228, 2005.
Song, P., Yang, Y., Barnes-Davies, M., Bhattacharjee, A., Hamann, M., Forsythe, I.D., Oliver, D.L., and Kaczmarek, L.K. Acoustic stimulation rapidly alters intrinsic excitability of auditory neurons, Nature Neurosci., 8: 1335-1342, 2005.
leonard.kaczmarek@yale.edu
|
|