NOISE FROM VOLTAGE-GATED ION CHANNELS MAY INFLUENCE NEURONAL DYNAMICSIN THE ENTORHINAL CORTEX

Neurons of the superficial medial entorhinal cortex (MEC), which deliv er neocortical input to the hippocampus, exhibit intrinsic, subthresho ld oscillations with slow dynamics. These intrinsic oscillations, driv en by a persistent Na+ current and a slow outward current, may help to generate the theta rhythm, a slow rhythm that plays an important role in spatial and declarative learning. Here we show that the number of persistent Na+ channels underlying subthreshold oscillations is relati vely small (<10(4)) and use a physiologically based stochastic model t o argue that the random behavior of these channels may contribute cruc ially to cellular-level responses. In acutely isolated MEC neurons und er voltage clamp, the mean and variance of the persistent Na+ current were used to estimate the single channel conductance and voltage-depen dent probability of opening. A hybrid stochastic-deterministic model w as built by using voltage-clamp descriptions of the persistent and fas t-inactivating Na+ conductances, along with the fast and slow K+ condu ctances. All voltage-dependent conductances were represented with nonl inear ordinary differential equations, with the exception of the persi stent Na+ conductance, which was represented as a population of stocha stic ion channels. The model predicts that the probabilistic nature of Na+ channels increases the cell's repertoire of qualitative behaviors ; although deterministic models at a particular point in parameter spa ce can generate either subthreshold oscillations or phase-locked spike s (but rarely both), models with an appropriate level of channel noise can replicate physiological behavior by generating both patterns of e lectrical activity for a single set of parameters. Channel noise may c ontribute to higher order interspike interval statistics seen in vitro with DC current stimulation. Models with channel noise show evidence of spike clustering seen in brain slice experiments, although the effe ct is apparently not as prominent as seen in experimental results. Cha nnel noise may contribute to cellular responses in vivo as well; the s tochastic system has enhanced sensitivity to small periodic stimuli in a form of stochastic resonance that is novel (in that the relevant no ise source is intrinsic and voltage-dependent) and potentially physiol ogically relevant. Although based on a simple model that does not incl ude all known membrane mechanisms of MEC stellate cells, these results nevertheless imply that the stochastic nature of small collections of molecules may have important effects at the cellular and network leve ls.