Kathy Engisch

Synaptic plasticity, the ability of synaptic transmission to be modulated up or down, over short time scales (milliseconds and seconds) and long time scales (minutes, hours, days, forever) underlies every aspect of normal and abnormal brain function. However, our understanding of the underlying mechanisms of synaptic transmission and its modulation is far from complete.

In our laboratory we study the basic mechanisms of neurotransmitter release in three different preparations. At the mouse nerve-muscle synapse (the neuromuscular junction) we use two electrode voltage clamp to record acetylcholine-activated currents in individual muscle fibers. In a neuroendocrine cell from the adrenal gland, adrenal chromaffin cells, we use perforated patch clamp to record tiny increases in cell capacitance that occur when vesicle membrane adds to the plasma membrane surface area. We also use carbon fiber amperometry to detect released norepinephrine and epinephrine from individual adrenal chromaffin cells. More recently we have added cultures of cortical neurons to our repertoire. Here we can record spontaneously occurring synaptic currents that arise from release of glutamate-containing vesicles from presynaptic terminals. Our laboratory has used these three preparations to study the function of Rab3A, a small GTPase associated with the membrane of synaptic vesicles. We have found that Rab3a plays multiple roles in neurotransmitter release, including regulating release of vesicles during repetitive stimulation, and regulating the kinetics of the single release event itself.

Currently, our laboratory is very interested in one form of synaptic plasticity that we believe affects the way the nervous system responds to injury and loss of synaptic inputs. To mimic such an injury, we block the activity of neurons for prolonged periods of time. It is well known that neurons respond to such a dramatic loss in activity with changes that attempt to bring the activity of the neurons back to normal. We are studying one aspect of this response, the increase in the amplitude of the spontaneously occurring miniature synaptic event, which corresponds to the response of a neuron to the release of a single vesicle of neurotransmitter. We find that at the neuromuscular junction, the normal increase in the miniature current amplitude after activity blockade is abolished in mice expressing a mutant form of Rab3A.