Our research focuses broadly on the function of nerve terminals, both how their neurotransmitter-filled vesicles fuse with the plasma membrane and how their excitability regulates the entry of Ca2+ to trigger membrane fusion. Our investigations of presynaptic mechanisms often take us into detailed studies at the molecular level, but we also venture in the opposite direction into questions about neural circuitry. To address these questions we employ the electrophysiological methods of patch clamping and amperometry, as well as a variety of forms of microscopy to image voltage and Ca2+.
Studies in PC12 cells, a powerful model system, have been especially productive in providing insight into the basic mechanism of Ca2+-triggered exocytosis. We have adapted the classical ideas of single ion channel mechanisms to the study of the fusion pore. This fusion pore spans both the vesicle and plasma membranes and in many ways behaves like an ion channel. We measure the flux through single fusion pores with amperometry and the conductance of single fusion pores by performing phase-lock measurements with a patch clamp amplifier. Experiments with these methods (in collaboration with Ed Chapman of this department) have indicated which proteins form the fusion pore and which proteins control their opening and expansion.
Fig. 1. An amperometry recording (below) signals three successive stages in exocytosis (above). The SNARE proteins, which play an essential role in exocytosis, are shown in different hypothetical configurations.
We also do experiments on the posterior pituitary, and have used this preparation to investigate presynaptic excitability. We have identified and characterized the ion channels in pituitary nerve terminals and shown how various signaling systems can target these ion channels for modulation. Present efforts focus on the sigma receptor, which modulates several ion channels (in collaboration with Arnold Ruoho of the Pharmacology Department), and the NO/cGMP signaling system, which produces a unique use-dependent enhancement of excitability. We are also imaging intra-terminal Ca2+ with two-photon microscopy in order to characterize the cytoplasmic Ca2+ buffers and explore how the spatial dynamics of Ca2+ controls the time course of release.
To relate what we learn at the molecular and cellular levels to neural circuit function we image electrical activity. Brain slices stained with a voltage sensitive dye can be imaged to follow the flow of electrical activity through a complex, intact neural circuit. This method is particularly powerful in detecting subtle variations in synaptic plasticity, and we have shown that long-term potentiation in hippocampal slices exhibits a complex form of spatial heterogeneity. We are also initiating a voltage imaging study of the superior colliculus (in collaboration with Michele Basso of this department), and we are attempting to develop genetically encoded voltage imaging probes (in collaboration with Baron Chanda of this department).
Fig. 2. A hippocampal slice stained with voltage sensitive dye (left) was imaged. Blue traces are optical signals that report electrical activity at each location. To image synaptic plasticity (right) theta bursts were applied and a difference map was constructed.
- Johannessen, M., Fontanilla, D., Mavlutov, T., Ruoho, A. E., Jackson, M. B. Antagonist Action of Progesterone at Sigma Receptors in the Modulation of Voltage-Gated Sodium Channels. American Journal of Physiology - Cell Physiology 300:C328-C337 (2011).
- Wang, D. Zhang, Z. Chanda, B. Jackson, M. B. Improved probes for hybrid voltage sensor imaging. Biophys. J. 99:2355-65 (2010).
- Vokoun, C. R., Jackson, M. B., Basso, M. A. Intra and Interlaminar Activity within the Rodent Superior Colliculus Visualized with Voltage Imaging. J. Neurosci. 30:10667-10682 (2010)
- Zhang, Z., Hui, E., Chapman, E. R., Jackson, M. B. Regulation of Exocytosis and Fusion Pores by Synaptotagmin-Effector Interactions. Mol. Biology Cell 21: 2821-31 (2010)
- Jackson, M. B. SNARE Complex Zipping as a Driving Force in the Dilation of Proteinaceous Fusion Pores. J. Membr. Biology 235: 89-100 (2010)
- Zhang, Z. Jackson, M. B. Membrane Bending Energy and Fusion Pore Kinetics in Ca2+-Triggered Exocytosis. Biophys. J. 98: 2524-2534 (2010).
- Carnally, M. S., Johannessen, M., Henderson, R. M., Jackson, M. B., Edwardson, J. M. Demonstration of a direct interaction between sigma-1 receptors and acid-sensing ion channels. Biophys. J. 98: 1182-91(2010).
- Zhang, Z., Zhang, Z., Jackson, M.B. (2010) Synaptotagmin IV modulation of vesicle size and fusion pores in PC12 cells. Biophys. J. 98: 968-978
- Zhang, Z., Hui, E., Chapman, E. R., Jackson, M. B. Synaptotagmin-Phosphatidylserine Interactions in the Regulation of Fusion Pores During in Ca2+-Triggered Exocytosis. Mol Biology Cell 20:586-95 (2009).
- Jackson, M. B. Minimum Membrane Bending Energies of Fusion Pores. J. Membr. Biology 231:101-115 (2009). PMC2833281
- Dean, C., Liu, H., Dunning, F. M., Chang, P. Y., Jackson, M. B., and Chapman, E. R. Synaptotagmin-IV is recruited to synapses by activity and scales synaptic strength pre and post-synapticaly. Nature Neurosci. 12:767-776 (2009).
- Johannessen, M. Ramachandran, S. , Riemer, L. , Ramos-Serrano, A., Ruoho, A. E., Jackson, M. B. Voltage-Gated Sodium Channel Modulation by Sigma Receptors in Cardiac Myocytes and Heterologous Systems. American Journal of Physiology - Cell Physiology 296:1049-57 (2009).
- Fontanilla, D., Johannessen, M., Hajipour, A. R., Cozzi, N. V., Jackson, M. B., Ruoho, A. E. N, N'-dimethyltryptamine (DMT) as an endogenous ligand for the sigma-1 receptor. Science 323:934-7 (2009).
- Zhang, Z., Bhalla, A., Dean, C., Chapman, E. R., Jackson, M. B. Synaptotagmin IV: a multifunctional regulator of peptidergic nerve terminals. Nature Neurosci. 12:163-172 (2009).
- Muroi, Y., Theusch, C. M., Czajkowski, C., Jackson, M. B. Distinct structural changes in the GABAA receptor elicited by pentobarbital and GABA. Biophys. J. 96:499-509 (2009).
- Zhang, Z. and Jackson, M. B. Temperature dependence of fusion kinetics and fusion pores in Ca2+-triggered exocytosis from PC12 cells. J. Gen. Physiol. 131: 117-124 (2008).
- Zhang, Z., Klyachko, V. and Jackson, M. B. Blockade of phosphodiesterase type 5 enhances rat neurohypophysial excitability and electrically-evoked oxytocin release. J. Physiol. In Press (2007).
- Chang, P. Y., Taylor, P. E., and Jackson, M. B. Voltage Imaging Reveals the CA1 Region at the CA2 Border as a Focus for Epileptiform Discharges and Long-Term Potentiation in Hippocampal Slices. J. Neurophysiol. In Press (2007).
- Chang, P. Y. and Jackson, M. B. Heterogeneous Spatial Patterns of Long-Term Potentiation in Hippocampal Slices. J. Physiol. 576: 427-443 (2006).
- Muroi, Y., Czajkowski, C., Jackson, M.B. Local and global ligand-induced changes in the structure of the GABAA receptor. Biochem. 45: 7013-7022 (2006).
- Han, X. and Jackson, M. B. Structural Transitions in the Synaptic SNARE Complex during Ca2+ Triggered Exocytosis. J. Cell Biol. 172: 281-293 (2006).
- Wang, C.-T., Bai, J. Chang, P. Y., Chapman, E. R., Jackson, M. B. Synaptotagmin-Ca2+ Triggers Two Sequential Steps in Regulated Exocytosis in rat PC12 cells: Fusion Pore Opening and Fusion Pore Dilation. J. Physiol., 570.2: 295-307 (2006).
- Han, X. and Jackson, M. B. Electrostatic interactions between the syntaxin membrane anchor and neurotransmitter passing through the fusion pore. Biophys. Lett. 88: L20-22 (2005).
Abstract | Full Text | PDF
- Han, X., Wang, C.-T., Bai, J., Chapman, E. R., Jackson, M. B. Transmembrane segments of syntaxin line the fusion pore of Ca2+-triggered exocytosis. Science 304: 289-292 (2004).
Abstract | Full Text | PDF
- Wang, C.-T., Lu, J.-C., Bai, J., Chang, P.-Y., Martin, T. F. J., Chapman, E. R. and Jackson, M. B. Different domains of synaptotagmin control the choice between kiss-and-run and full-fusion. Nature 424: 943-947 (2003).
Abstract | Full Text| PDF
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