In contrast to the limited response properties observed under normal experimental conditions, spinal motoneurons generate complex firing patterns, such as Ca2+-dependent regenerative spiking and plateaus, in the presence of certain neurotransmitters and ion-channel blockers. We have developed a quantitative motoneuron model, based on turtle motoneuron data, toinvestigate the roles of specific ionic currents and the effects of their soma and dendritic distribution in generating these complex firing patterns. In addition, the model is used to explore the effects of multiple ion channel blockers and neurotransmitters that are known to modulate motoneuron firing patterns. To represent the distribution of ionic currents across the soma and dendrites, the model contains two compartments. The soma compartment, representing the soma and proximal dendrites, contains Hodgkin-Huxley-like sodium (INa) and delayed rectifier K+ (IK-dr) currents, an N-like Ca2+ current (ICa-N), and a calcium-dependent K+ current [IK(Ca)]. The dendritic compartment, representing the lumped distal dendrites, contains, in addition to ICa-N and IK(Ca) as in the soma, a persistent L-like calcium current (ICa-L). We determined kinetic parameters for INa, IK-dr, ICa-N, and IK(Ca) in order to reproduce normal action-potential firing observed in turtle spinal motoneurons, including fast and slow afterhyperpolarizations (AHPs) and a linear steady-state frequency-current relation. With this parameter set as default, a sequence of pharmacological manipulations were systematically simulated. A small reduction of IK-dr [mimicking the experimental effect of tetraethylammonium (TEA) in low concentration] enhanced the slow AHP and caused calcium spiking (mediated by ICa-N) when INa was blocked. Firing patterns observed experimentally in high TEA [and tetrodotoxin (TTX)], namely calcium spikes riding on a calcium plateau, were reproduced only when both IK-dr and IK(Ca) were reduced. Dendritic plateau potentials, mediated by ICa-L, were reliably unmasked when IK(Ca) was reduced, mimicking the experimental effect of the bee venom apamin. The effect of 5-HT, which experimentally induces the ability to generate calcium-dependent plateau potentials but not calcium spiking, was reproduced in the model by reducing IK(Ca) alone. The plateau threshold current level, however, was reduced substantially if a simultaneous increase in ICa-L was simulated, suggesting that serotonin (5-HT) induces plateau potentials by regulating more than one conductance. The onset of the plateau potential showed significant delays in response to near-threshold, depolarizing current steps. In addition, the delay times were sensitive to the current step amplitude. The delay and its sensitivity were explained by examining the model's behavior near the threshold for plateau onset. This modeling study thus accurately accounts for the basic firing behavior of vertebrate motoneurons as well as a range of complex firing patterns invoked by ion-channel blockers and 5-HT. In addition, our computational...

Spatiotemporal pattern formation in neuronal networks depends on the interplay between cellular and network synchronization properties. The neuronal phase response curve (PRC) is an experimentally obtainable measure that characterizes the cellular response to small perturbations, and can serve as an indicator of cellular propensity for synchronization. Two broad classes of PRCs have been identified for neurons: Type I, in which small excitatory perturbations induce only advances in firing, and Type II, in which small excitatory perturbations can induce both advances and delays in firing. Interestingly, neuronal PRCs are usually attenuated with increased spiking frequency, and Type II PRCs typically exhibit a greater attenuation of the phase delay region than of the phase advance region. We found that this phenomenon arises from an interplay between the time constants of active ionic currents and the interspike interval. As a result, excitatory networks consisting of neurons with Type I PRCs responded very differently to frequency modulation compared to excitatory networks composed of neurons with Type II PRCs. Specifically, increased frequency induced a sharp decrease in synchrony of networks of Type II neurons, while frequency increases only minimally affected synchrony in networks of Type I neurons. These results are demonstrated in networks in which both types of neurons were modeled generically with the Morris-Lecar model, as well as in networks consisting of Hodgkin-Huxley-based model cortical pyramidal cells in which simulated effects of acetylcholine changed PRC type. These results are robust to different network structures, synaptic strengths and modes of driving neuronal activity, and they indicate that Type I and Type II excitatory networks may display two distinct modes of processing information.

Various nonlinear regenerative responses, including plateau potentials and bistable repetitive firing modes, have been observed in motoneurons under certain conditions. Our simulation results support the hypothesis that these responses are due to plateau-generating currents in the dendrites, consistent with a major role for a noninactivating calcium L-type current as suggested by experiments. Bistability as observed in the soma of low- and higher-frequency spiking or, under TTX, of near resting and depolarized plateau potentials, occurs because the dendrites can be in a near resting or depolarized stable steady state. We formulate and study a two-compartment minimal model of a motoneuron that segregates currents for fast spiking into a soma-like compartment and currents responsible for plateau potentials into a dendrite-like compartment. Current flows between compartments through a coupling conductance, mimicking electrotonic spread. We use bifurcation techniques to illuminate how the coupling strength affects somatic behavior. We look closely at the case of weak coupling strength to gain insight into the development of bistable patterns. Robust somatic bistability depends on the electrical separation since it occurs only for weak to moderate coupling conductance. We also illustrate that hysteresis of the two spiking states is a natural consequence of the plateau behavior in the dendrite compartment.