Meyer Jackson

Biophysics of the Synapse

Membranes play a key role in neuronal signaling at multiple levels. Membrane fusion controls synaptic release; ion flux through membranes controls electrical signaling in neurons. These membrane processes come into play as neurons communicate, and as complex neural circuits in different brain regions encode, process, and store information. My laboratory has two major programs of research focused on opposite ends of the synaptic spectrum. At one end we study the molecular mechanisms of synaptic release and at the other end we study the electrical activity of neural circuits. Approaching synapses from these two poles creates a synergy, and makes my laboratory a vibrant environment for neuroscience research.

Our study of synaptic release focuses on fusion pores, a fluid connection that forms between the vesicle interior and extracellular space immediately after the plasma and vesicle membranes fuse. Measurements of fusion pores enable us to probe their structure and learn what controls their opening, closing, and expansion. We have shown that Ca²⁺ binding to presynaptic Ca²⁺ sensors in the synaptotagmin family alters the dynamic transitions of fusion pores. We have shown that the transmembrane domains of the synaptic SNARE proteins syntaxin and synaptobrevin alter the flux, conductance, and stability of nascent fusion pores in a manner consistent with a model of the pore formed by the membrane spanning parts of these proteins. By perturbing different proteins of the exocytotic apparatus and probing fusion pore status we are elucidating the fundamental mechanisms of synaptic release.

At the other end of the spectrum we use both synthetic and genetically-encoded optical sensors of membrane potential to image electrical activity of many neurons simultaneously in intact neural circuits. Synthetic voltage sensors are being used to image spatial patterns and test basic models of information storage and recall. Genetically-encoded voltage sensors are being used to target selected cell types, dissect different elements of a neuronal circuit, and study their connections. By targeting voltage sensors to genetically defined populations of neurons we are probing neural circuit microstructure and determining how each type of neuron contributes to the emergent properties of neuronal circuits.

hVOS probe expression in axons. A. A two-photon image of a hippocampal slice from a thy1-hVOS 2.0 transgenic mouse at low magnification shows the pattern of probe expression. Note the strong probe expression in the inner molecular layer (iml) of the dentate gyrus (DG) and mossy fibers in the stratum lucidum (sl) of the CA3 region (arrowheads). B. Diagram illustrating the labeled axons in (A) based on known hippocampus anatomy. Axons of hilar mossy cells (magenta) are located in the iml; the sl contains axons of dentate granule cells (cyan).  C. At higher magnification two-photon microscopy reveals mossy fiber axons (marked by red arrowheads) in the sl. D. STED microscopy reveals probe-expressing mossy cell axons (marked by red arrowheads) in the iml. E. hVOS 1.5 tethered by a C-terminal h-ras motif to the plasma membrane is illustrated on the left. In the sl this probe registered a spike-like axonal action potential (AP) followed by a synaptic response. Black, control aCSF; Red, aCSF without calcium; Blue, after return to control aCSF with calcium. Calcium removal reversibly blocked the later synaptic component but left the AP unchanged. F. hVOS 2.0 has the same C-terminal membrane linkage as in hVOS 1.5, as well as an N-terminal link derived from GAP-43 (both termini are on the same side of the beta-barrel). hVOS 2.0 only registered an axonal AP with no late synaptic component. The AP was unaffected by calcium removal in both hVOS 1.5 and hVOS 2.0 recordings. Stimulus = 200 µA. [DPA] = 4 µM. 10-trial averages.

from Ma et al eNeuro 4: e0146-17, 2017.

Lab website

Representative publications:

Jackson, M. B. SNARE Complex Zipping as a Driving Force in the Dilation of Proteinaceous Fusion Pores. J. Membr. Biology235: 89-100 (2010).

Jackson, M. B. Recall of Spatial Patterns Stored in a Hippocampal Slice By Long-Term Potentiation. J. Neurophysiol. 110: 2511-19 (2013).

Bayguinov, P. O., Ma, Y., Gao, Y., Zhao, X., Jackson, M. B. Imaging Voltage in Genetically-Defined Neuronal Subpopulations with a Cre Recombinase-Targeted Hybrid Voltage Sensor. J Neurosci 37:9305-19 (2017). Cover image.

Chang, C.-W., Chiang, C.-W., and Jackson, M. B. Fusion Pores and Their Control of Neurotransmitter and Hormone Release. J. Gen. Physiol. 149:301-322 (2017).

Chiang, C. W., Chang, C. W., Jackson, M. B. The Transmembrane Domain of Synaptobrevin Influences Neurotransmitter Flux Through Synaptic Fusion Pores. J Neurosci 38:7179-7191 (2018). Cover image