Mark R. Plummer, Ph.D.
Associate Professor of Cell Biology and Neuroscience
Rutgers University

Address: Nelson Laboratories, 604 Allison Road, Piscataway, NJ 08854-8082
Phone: (732) 445-0422
FAX: (732) 445-5870
Email: mplummer@rci.rutgers.edu
Home page: http://lifesci.rutgers.edu/~mplummer/lab/index.htm

Contents

I. Overview of research interests
II. Voltage-dependent potentiation of the Lp calcium channel
III. Neurotrophin modulation of synaptic strength
IV. Recent publications

Overview of Research Interests

The sophisticated cognitive functions of the human brain reside in complex connections of cells in the central nervous system. Communication between nerve cells, via synaptic transmission, is a highly plastic process, with signal strength waxing and waning as new information is processed and stored. One of the major challenges of modern neuroscience is to understand synaptic plasticity, with the hope that this will lead to deeper insights about our own ability to learn and remember.

Research in my laboratory has been directed toward understanding mechanisms that initiate and regulate changes in synaptic strength. Our recent work, described in more detail below, has focused on elucidating fundamental biophysical characteristics of membrane proteins that control an early event in the process: the influx of extracellular calcium into the interior of nerve cells. Rapid calcium entry in nerve cells is accomplished by proteins known as calcium channels, which can be opened to allow calcium passage. Calcium channels can be activated by electrical signals (changes in intracellular voltage) or by chemical ones (such as the neurotransmitter glutamate). By working with isolated neurons in tissue culture, we have recently identified a new type of voltage-gated calcium channel and a novel effect of the brain-derived neurotrophic factor (BDNF) on the NMDA receptor. Future studies will involve expanding the functional context in which these proteins are examined, moving from isolated cells to the sophisticated neuronal assemblies found in brain slices. The ultimate goal that guides us will be to answer the question of how the properties and modulation of calcium-permeable membrane proteins lead to stimulus-specific control of synaptic strength.

Voltage-dependent potentiation of the Lp calcium channel

Calcium channel activity can be dynamically influenced in a variety of ways. One kind of modulation does not depend on application of external compounds – it is elicited by changes in membrane potential. This phenomenon has been described as voltage-dependent potentiation, referring to a transient enhancement of channel activity produced by a "conditioning" depolarization. It is associated primarily with dihydropyridine (DHP)-sensitive calcium channels, and has been found in adrenal chromaffin cells, cardiac myocytes, and skeletal muscle.

In hippocampal neurons, we have observed a type of calcium channel potentiation distinct from that found in non-neural tissue. It can be elicited by relatively low voltages, survives transient hyperpolarization, and is observed in the presence of DHP agonists. We have suggested that this low-voltage potentiation can be attributed to a novel kind of DHP-sensitive calcium channel (Lp channel) that is distinct from the "standard" L-type calcium channel (Ls channel) in hippocampal neurons. The two channel types can be distinguished from one another on the basis of conductance, mean open time, and characteristic gating patterns. Furthermore, we have shown that DHP-sensitive calcium channels in hippocampal neurons display two distinct kinds of calcium channel potentiation which differ in their voltage dependence and duration. One type is a low-voltage form that is unique to Lp calcium channels. The second is a high-voltage form similar to that observed in cardiac L-type channels which is present in both hippocampal Ls and Lp channels.

During the course of our work, we noticed that recordings from some cells showed more Lp activity than others, suggesting that channel activity may be subject to extrinsic modulation. To examine this issue in detail, as well as to learn more about the mechanism of Lp potentiation, we did a series of experiments on cAMP-dependent regulation of DHP-sensitive calcium channels in hippocampal neurons. We found that membrane-permeable analogs increase Ls and Lp channel availability, but do not affect Lp potentiation. These data confirm work by other investigators on cAMP modulation of neuronal calcium channels, and also show that Lp potentiation, unlike that in adrenal chromaffin cells and skeletal muscle, is intrinsic to the channel and does not require phosphorylation.

An important question regarding Lp channels concerns the physiological function of voltage-dependent potentiation. One possibility is that it mediates some form of synaptic plasticity. This would mean that the stimulus specificity required to elicit changes in synaptic strength would be determined by the voltage protocol necessary to evoke Lp potentiation in a way analogous to biophysical features of the NMDA receptor being intimately involved in the induction of LTP.

Neurotrophin modulation of synaptic strength

Neurotrophins are important regulators of the survival, development, and differentiation of specific neuronal populations, effects that generally occur over the course of hours, or even days. It is now becoming clear, however, that neurotrophins can have powerful effects on the electrical activity of nerve cells. We have found that exposure of basal forebrain neurons to NGF can increase calcium current density. More recently, we have shown that acute application of BDNF can rapidly increase the spontaneous firing rate of cultured hippocampal neurons and enhance synaptic transmission. The actions of BDNF are thought to be mediated by the TrkB tyrosine kinase receptor, which is expressed throughout the hippocampus. Bath application of the specific trk tyrosine kinase inhibitor K-252a had no effect on baseline synaptic currents and completely blocked the effect of BDNF. In addition, tests of neurotrophin specificity showed that the related neurotrophins nerve growth factor (NGF) and neurotrophin-3 (NT-3) had no significant effects on synaptic currents, suggesting that the response is mediated selectively via the TrkB receptor.

To continue these studies, we need to understand how BDNF is exerting its effect. We are currently using iontophoretically applied glutamate and subtype-specific glutamate receptor agonists to test the hypothesis that BDNF exerts its action by increasing the sensitivity of the NMDA receptor. These results illustrate a marvelous multiplicity of function for neurotrophins. On the one hand, these substances are exceptionally important as growth factors, evoking long-term increases in cell survival and outgrowth. On the other hand, they also can increase the signaling strength of nerve cells, thus providing a substrate for activity-dependent enhancement in synapse formation.

There is now considerable evidence for the involvement of calcium channels and glutamate receptors in the dynamic control of synaptic strength. There remain, however, enormous gaps in our knowledge of how synaptic plasticity works, and how changes in synaptic strength actually manifest themselves in altered behavior. By having identified a novel voltage-gated calcium channel and by discovering an unknown action of the neurotrophin BDNF, we have gained new insights into potential molecular controls for eliciting changes in synaptic efficacy. This is the kind of work needed to relate ion channel biophysical phenomena to the control of synaptic activity in the brain.

Recent publications

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Last updated: Wednesday, September 04, 2002