This study investigated the effect that morphology differences alone can have on the spiking behavior of biophysically realistic multicompartmental models 
of morphologically reconstructed granule cells from epileptic and control rat DG 
. The models had the same types of ion channels and the same distributions of conductance densities over their dendritic segments 
. The only difference between them was their morphology, which is associated with the two rat samples used: control and PILO. Further sources of distinction were introduced by two pairs of criteria that allowed us to divide dendrites into segments, distance-1/distance 2 and pruning/shrinking, resulting in 23
8 different samples of cell models: PILO-pruned-distance 1, PILO-pruned-distance 2, PILO-shrank-distance 1, PILO-shrank distance 2, Control-pruned-distance 1, Control-pruned-distance 2, Control-shrank-distance 1 and Control-shrank-distance 2.
Our simulation results allow a prediction of what could be found in electrophysiological studies with newly born DG GCs following SE induced by PILO. The prediction is that these cells are less excitable than the control ones. Moreover, this decrease in cell excitability can be a consequence of the morphological differences between PILO and control cells alone, because in both groups we placed the same ion channel conductances, densities and distributions.
Although in our simulations the average values of the input resistances of PILO and Control cell models were not significantly different, the average value for PILO cells was slightly smaller than the one for Control cells, and this is also consistent with the prediction of smaller excitability of PILO cells.
The strategy of using different numbers of electrodes placed randomly in different dendritic regions makes it possible to evaluate the effects of the morphological differences in a more accurate way. With this strategy we evaluate how the same stimulus intensity can provoke different patterns of response depending on its distributions in the dendritic tree. Our finding that there are differences in cell response depending on both the number of electrodes and the local of stimulation confirms previous studies 
The major contribution of the current study is that it is possible to discriminate the level of excitability between control and PILO cells based on morphology alone. We found that depending on the dendritic region where the stimuli (electrodes) are placed, the response (firing frequency) of PILO cells is smaller than the one of control cells. This result is significant for pruned-distance 2 cell models stimulated in the IML. This result is important because it suggests that the excitability of PILO cells is highly dependent on the specific area of their dendritic trees which serve as target for synaptic input. For example, from Arisi and Garcia-Cairasco 
it is clear that in SE induced by PILO the mossy fiber axon collaterals sprouted mostly in coincidence with the IML, where the shortest dendritic ramifications end.
It is important to mention that even though we used the same distributions of maximum ionic conductance densities and passive electrophysiological properties across dendritic segments in our cell models, because of the differences in dendritic lengths between control and PILO cells the actual dendritic surface areas reached by currents injected in the three molecular layers (IML, MML and OML) were different for the two cell groups. This implies that, effectively, the number of ionic channels activated by current injection in the same molecular layer, e.g. IML, was different from control to PILO cells (this was reflected, although not significantly, in the small difference in input resistance found between the two cell types). Moreover, this difference also depends on the segmentation criterion used, and this is why the excitability reduction was more pronounced in pruned models than in shrank models.
Therefore, even in the absence of explicit changes in the maximal ionic conductance densities, morphological alterations caused by SE induced by PILO may be accompanied by changes in these densities (from the point of view of the mossy fibers that innervate the IML). We propose that these changes are partly responsible for the excitability reduction in PILO cells observed in our study.
Newborn DG GCs after SE
may also have explicit changes in the ionic channels and their density distributions 
. Because of this, there may be a coordinated effect of changes in both morphology and channel densities upon the firing behavior of DG GCs. The present study may thus be considered a first step to attempt to understand the role of morphological changes in DG GCs after SE. Therefore, future studies to investigate the possible coordinated effect between changes in both dendritic morphology and densities and distributions of ion channels on the electrophysiological behavior of DG GCs after SE are needed.
It is interesting that despite the differences observed between cells built with distance 1 and distance 2 criteria, both groups of PILO cell models showed less excitability than control groups. This finding suggests two possible scenarios in which the effects of the morphological differences can be mitigated or accentuated depending on the way in which the ionic conductances and densities are distributed. In the first, using the distance 1 criterion, for which the distribution of ionic conductances and densities did not take into consideration the dendrite length and considered only its beginning position, the excitability reduction is moderate. In the second, using the distance 2 criterion for which the distribution of biophysical properties considered the length of the dendrite there is an accentuated reduction in the cell excitability. This suggests that longer dendrites may have a more important role in the decrease of excitability than short dendrites that grow close to soma, because the differences between distance 1 and distance 2 models are concentrated in longer dendrites, which have different distance 1 and distance 2 values and, therefore, different distributions of biophysical properties.
Also, the pruning and shrinking criteria offer two possible scenarios for the effects of the morphological differences: in the first one the shorter dendrites of the PILO cells may be a product of pruning, while in the second one these dendrites may be a product of shrinking. In our simulations the pruning criterion showed more differences between control and PILO cells than the shrinking criterion. Therefore, the morphological pattern of pruned DD dendrites in PILO cell models produces decreased excitability, which could be tested in the lab using, for example, techniques of neuronal growth cone identification 
applied in newly born DG GCs 
A final commentary can be made on the potential causes of decreased excitation of the GCs in an epileptogenic circuit or network. Jakubs et al. 
have recently shown in hippocampal slide preparations that new DG GCs born into the epileptic environment received increased inhibitory input and have a lower mean frequency of spontaneous excitatory postsynaptic currents. Also, Kobayashi and Buckmaster 
and Otis et al. 
have found an increase in the GABAA
receptors in dentate GCs in epilepsy animal models, which enhances the inhibitory effects upon these cells. In the same direction Santos et al. 
have shown that GC after SE induced by PILO display significant reductions in spine density. All these findings match with the reduction of excitability exhibited by our computational models.
Although our computational modeling is based upon single neuron morphologies, it is clear that network modeling is needed in order to better understand the role of the newly generated cells in an environment, as close as possible to physiology. In this direction, elegant examples such as the DG network model developed by Santhakumar et al. 
, that evaluated the mossy fiber axon collaterals sprouting, or the models developed by Aimone 
Weisz and Argibay 
, that explore the effects of neurogenesis in the DG, are excellent starting points.
Summarizing, our results predict a decrease in the excitability in PILO cells that emerge after SE. But how do we explain this kind of prediction? Why do these cells need more stimulation to reach the same response? A possible hypothesis is that this reduction in excitability due to morphological alterations is a protective mechanism that, in addition with the increase of inhibition 
and reduction of spine density 
, allows the cell to be able to cope with the increased excitation that is present after SE 
In this context, changes in the morphology – such as the fiber sprouting, which increases the stimulation 
in the IML – could be accompanied by changes in the dendritic tree that provoke decrease of cell excitability as a compensatory mechanism. This is in agreement with the theory of the abnormal neural networks in epilepsy 
. Therefore, it will be extremely important to evaluate the effects of this reduced excitability of newly born GC PILO cells in a network context. Thus, our next logical step would be to build a network model of the DG and to test the effects of the insertion of the new GCs with altered morphology in the circuit behavior.