This should affect INaP-dependent bursting ( Rybak et al., 2003). To theoretically investigate the effect of changing [Ca2+]o and [K+]o on neuronal bursting behavior, we used a single-compartment computational model of the Hb9 cell. In this model, we explicitly simulated a negative voltage shift of INaP activation with a reduction of [Ca2+]o ( Figure 3A). For VmNaP1/2 = –52 mV (at [K+]o = 6 mM), the model exhibited tonic spiking activity ( Figure 3B, top). Bursting

activity appeared at VmNaP1/2 = –53 mV ( Figure 3B, middle), and further shifting VmNaP1/2 to the left produced stable bursting with higher spiking frequency selleck compound within bursts ( Figure 3B, bottom). As expected, depolarizing the neuron by injecting current increased bursting frequency ( Figure S4, top). Bursts disappeared when the conductance of

INaP was set to 0 (to simulate the effect of riluzole, Figure S4, bottom). To investigate how random distribution of neuronal parameters could selleck kinase inhibitor affect neuron bursting properties and the relative number of pacemaker neurons involved in population bursting, we simulated a population of 50 uncoupled neurons. To provide a necessary heterogeneity in bursting properties of neurons, we randomly distributed the base values of neuronal VmNaP1/2 (i.e., these values at [Ca2+]o = 1.2 mM and [K+]o = 4 mM) among neurons using the uniform distribution within the interval [−53, −48] mV. An additional heterogeneity was set by normal distribution of all conductances, including that for INaP. The average values and variances used for all conductances can be found in the Supplemental Experimental Procedures. Because of the random distributions

used, some neurons with more negative VmNaP1/2 and/or higher values of INaP maximal conductance were intrinsic bursters, whereas the Carnitine dehydrogenase remaining neurons had no bursting capabilities. This was equivalent to our experimental data showing that bursting Hb9 interneurons had more negative values of the activation threshold and half-activation voltage for INaP than nonbursting neurons ( Table S3). After parameter distributions, simulations were run to check the ability of each neuron to generate bursts with changes in [Ca2+]o and [K+]o and to determine the percentage of bursting cells in the population at each level of [Ca2+]o (from 1.2 to 0.9 mM with 0.1 mM steps) and [K+]o (from 4.0 to 6.0 mM with 0.5 mM steps). Each 0.1 mM decrease in [Ca2+]o reduced VmNaP1/2 in all neurons by 1 mV (hence shifting INaP activation to more negative values of voltage); each 0.5 mM increase in [K+]o resulted in the corresponding reduction of EK and EL (see above). The results are summarized in Figure 3C. Specifically, none of the neurons exhibited bursting at base levels of [Ca2+]o and [K+]o (1.2 and 4 mM, respectively).