The original model predicted BAY 73-4506 supplier a decrease in the frequency of single-cell membrane-potential oscillations along the dorsoventral axis of MEC, in parallel with the decrease in the spatial frequency of the grid (O’Keefe and Burgess, 2005). Such a frequency change was subsequently demonstrated in whole-cell patch-clamp recordings of medial entorhinal layer II neurons (Giocomo et al., 2007). Moreover, consistent with the prediction that oscillations are key to generating

stable grid cell representations, loss of the global theta rhythm by medial septum inactivation has been shown to result in loss of periodicity in the firing locations of grid cells (Brandon et al., 2011 and Koenig et al., 2011). As predicted, the frequency of the field theta rhythm has been found to be more sensitive to changes in the rat’s running speed in dorsal compared to ventral MEC (Jeewajee et al., 2008), and ventral MEC cells have been reported to fire only on every other theta peak (theta skipping) (Deshmukh et al., 2010), in agreement with an oscillatory-interference model implemented in a resonant network (Zilli and Hasselmo, 2010). It should be noted, however, that these experimental results can in principle also learn more be obtained by mechanisms other than oscillatory interference. Recently, multiple criticisms of the

first generation of oscillatory-interference models have been raised. For example, several papers have criticized the oscillatory-interference approach for modeling biological oscillators as perfect sinusoids (Giocomo and Hasselmo, 2008a, Welinder et al., 2008 and Zilli et al., 2009). In contrast to the modeled oscillations, in vitro slice recordings indicate that membrane-potential oscillations show a high degree of noise (Dudman and Nolan, 2009 and Zilli et al., 2009), variance in frequency (Giocomo

and Hasselmo, 2008a), and significant attenuation in high-conductance conditions, which may occur during realistic in vivo levels of synaptic input (Fernandez and White, 2008). Computational simulations indicate that accumulating noise interferes with the grid pattern. The rate at which a grid cell’s Terminal deoxynucleotidyl transferase spatial pattern drifts from its correct position can be calculated based on the variance of the oscillator (Welinder et al., 2008 and Zilli et al., 2009). The measured variance in persistent spiking neurons and membrane-potential oscillations is not able to keep the grid pattern stable for more than a few seconds (Welinder et al., 2008 and Zilli and Hasselmo, 2010), whereas the pattern is maintained for minutes in vivo ( Hafting et al., 2005). In addition, criticism has focused on the assumption that multiple, separate oscillations combine in the soma while maintaining independence in the dendrites (Remme et al., 2009).