JOURNAL d OF Vol. 74, No. NEUROPHYSIOLOGY 4, October 1995. Printed in U.S.A. Mferent Synaptic Drive of Rat Medial Nucleus Tractus Solitarius Neurons: Dynamic Simulation of Graded Vesicular Mobilization, Release, and non-NMDA Receptor Kinetics J. H. SCHILD, J. W. CLARK, C. C. CANAVIER, D. L. KUNZE, AND M. C. ANDRESEN Department of Molecular Physiology and Biophysics, Baylor College of Medicine; Department of Electrical and Computer Engineering, Rice University, Houston, Texas 77251-l 892; Department of Anatomy and Neurobiology, University of Texas Medical School, Houston 77030; and Department of Physiology, Oregon Health Sciences University, Portland, Oregon 97201-3098 SUMMARY AND CONCLUSIONS 1. We have developed a comprehensive mathematical model of an afferent synaptic connection to the soma of a medial nucleus tractus solitarius (mNTS ) neuron. Model development is based on numerical fits to quantitative data recorded in our laboratory. This work is part of a continuing collaborative effort aimed at identi- fying and characterizing the mechanisms responsible for the non- linear integrative properties of this first synapse in the baroreceptor reflex. 2. The complete model consists of three major parts: 1) a Hodg- kin-Huxley (HH) -type membrane model of the prejunctional sen- sory terminal bouton; 2) a multistage model describing vesicular storage, adenosine 3 ‘,5 ‘-cyclic monophosphate (CAMP) - and Ca2+-dependent mobilization, release and recycling; and 3) a HH- type membrane model of the postjunctional mNTS cell that in- cludes descriptions for a desensitizing non- N-methyl-D-aspartate (NMDA) ionic current that is responsible for the fast excitatory postsynaptic potentials (EPSPs) observed in mNTS cells. The membrane models for both the terminal bouton and the mNTS neuron are coupled to separate lumped fluid compartment models describing intracellular Ca2’ ion concentration dynamics. 3. Our modeling strategy is twofold. The first is to validate model performance by reproducing a wide variety of experimental data both from our laboratory and from the literature. The second and decay time of the EPSP, thereby affecting synaptic throughput. However, we demonstrate that, as the time course of neurotransmit- ter in the synaptic cleft decreases, the influence of desensitization should be somewhat diminished. As a result, the effective band- width of the synapse increases and becomes limited by the gating characteristics of the non-NMDA channel. 6. The model also includes a neuromodulatory aspect in that the frequency response of the synapse can be modulated by an adenylate cyclase-mediated regulatory mechanism. Although our simulations indicate the behavior of a limited number of possible neuromodulatory agents, the results demonstrate the pivotal role such agents could play in modifying synaptic transfer characteris- tics presynaptically. 7. Both continuous and burst-mode tract stimulation evoke pat- terns of action potentials in spontaneously active mNTS neurons that are mimicked very well by our model. Our simulations demon- strate that, as the rate of stimulation increases beyond -20-30 Hz, the inherent low-pass frequency-response characteristics of the synapse limit the overall dynamic range of the mNTS neuron, causing the postsynaptic cell to “entrain” at frequencies within its normal operating range. These results suggest that this first synapse in the baroreflex pathway is well suited for transmitting sustained low-frequency (i.e., 5 10 Hz) activity to mNTS neurons but cannot faithfully transmit high-frequency (i.e., 220 Hz) activity. is to explore the functional aspects of the model in order to gain a greater appreciation for the balance between presynaptic mecha- nisms (e.g., terminal membrane properties and vesicular dynamics) INTRODUCTION and postsynaptic mechanisms (e.g., non-NMDA receptor kinetics and neuronal dynamics) that underlie the afferent synaptic drive Our group is investigating the dynamic properties of sen- of mNTS neurons. sory afferent synaptic transmission in neurons within the 4. The model accurately reproduces EPSP dynamics recorded dorsomedial region of the nucleus of the tractus solitarius with the use of a wide range of stimulus protocols. The model (mNTS ) . The mNTS is an integral part of the basic circuitry can also mirror the unique pattern of graded frequency- and use- underlying the neural control of the circulation. Recent in- dependent reduction in peak EPSP magnitude observed experimen- vestigations from our laboratories are revealing the funda- tally through 60 s of constant, suprathreshold synaptic activation. mental properties of the individual neurons and neural cir- We demonstrate how vesicular mobilization, recycling, and recep- cuitry that constitute this medullary control center (Andresen tor kinetics can function synergistically in establishing synaptic transfer. Furthermore, we show that by allowing the aggregate rate and Yang 1995; Drewe et al. 1988, 1990; Kunze 1987; Men- of vesicle mobilization to respond in a use-dependent manner, it delowitz et al. 1995; Schild et al. 1993, 1994). Unfortu- is possible to compensate for the attenuating affects of desensitiza- nately, it is difficult to assess the functional significance of tion at elevated rates of stimulation. these individual observations in terms of the neural strata- 5. Our simulations indicate that the low-frequency characteris- gems underlying circulatory control, such as the baroreflex tics of this synapse are dominated by vesicular dynamics, whereas (Persson and Kircheim 1991) . Therefore we have turned to the high-frequency properties arise from a combination of Ca”+- mathematical modeling to explore potential network struc- dependent vesicular mobilization and the kinetics of the non- tures that may be involved in the processing of baroreceptor NMDA receptor. Desensitization can influence the peak magnitude inputs within the mNTS. However, we contend that, before 0022-3077/95 $3.00 Copyright 0 1995 The American Physiological Society 1529