Impaired neuronal operation through aberrant intrinsic plasticity in epilepsy.

OBJECTIVE: Patients with temporal lobe epilepsy often display cognitive comorbidity with recurrent seizures. However, the cellular mechanisms underlying the impairment of neuronal information processing remain poorly understood in temporal lobe epilepsy. Within the hippocampal formation neuronal networks undergo major reorganization, including the sprouting of mossy fibers in the dentate gyrus; they establish aberrant recurrent synapses between dentate granule cells and operate via postsynaptic kainate receptors. In this report, we tested the hypothesis that this aberrant local circuit alters information processing of perforant path inputs constituting the major excitatory afferent pathway from entorhinal cortex to dentate granule cells. METHODS: Experiments were performed in dentate granule cells from control rats and rats with temporal lobe epilepsy induced by pilocarpine hydrochloride treatment. Neurons were recorded in patch clamp in whole cell configuration in hippocampal slices. RESULTS: Our present data revealed that an aberrant readout of synaptic inputs by kainate receptors triggered a long-lasting impairment of the perforant path input-output operation in epileptic dentate granule cells. We demonstrated that this is due to the aberrant activity-dependent potentiation of the persistent sodium current altering intrinsic firing properties of dentate granule cells. INTERPRETATION: We propose that this aberrant activity-dependent intrinsic plasticity, which lastingly impairs the information processing of cortical inputs in dentate gyrus, may participate in hippocampal-related cognitive deficits, such as those reported in patients with epilepsy.

Synaptic kainate receptors in interplay with INaP shift the sparse firing of dentate granule cells to a sustained rhythmic mode in temporal lobe epilepsy.

Dentate granule cells, at the gate of the hippocampus, use coincidence detection of synaptic inputs to code afferent information under a sparse firing regime. In both human patients and animal models of temporal lobe epilepsy, mossy fibers sprout to form an aberrant glutamatergic network between dentate granule cells. These new synapses operate via long-lasting kainate receptor-mediated events, which are not present in the naive condition. Here, we report that in chronic epileptic rat, aberrant kainate receptors in interplay with the persistent sodium current dramatically expand the temporal window for synaptic integration. This introduces a multiplicative gain change in the input-output operation of dentate granule cells. As a result, their sparse firing is switched to an abnormal sustained and rhythmic mode. We conclude that synaptic kainate receptors dramatically alter the fundamental coding properties of dentate granule cells in temporal lobe epilepsy.

Dentate Granule Cells Recruited in the Home Environment Display Distinctive Properties.

The dentate granule cells (DGCs) play a crucial role in learning and memory. Many studies have described the role and physiological properties of these sparsely active neurons using different behavioral contexts. However, the morpho-functional features of DGCs recruited in mice maintained in their home cage (without training), considered as a baseline condition, have not yet been established. Using fosGFP transgenic mice, we observed ex vivo that DGCs recruited in animals maintained in the home cage condition are mature neurons that display a longer dendritic tree and lower excitability compared with non-activated cells. The higher GABAA receptor-mediated shunting inhibition contributes to the lower excitability of DGCs activated in the home environment by shifting the input resistance towards lower values. Remarkably, that shunting inhibition is neither observed in non-activated DGCs nor in DGCs activated during training in virtual reality. In short, our results suggest that strong shunting inhibition and reduced excitability could constitute a distinctive neural signature of mature DGCs recruited in the context of the home environment.

Dynamic control of hippocampal spatial coding resolution by local visual cues.

The ability to flexibly navigate an environment relies on a hippocampal-dependent cognitive map. External space can be internally mapped at different spatial resolutions. However, whether hippocampal spatial coding resolution can rapidly adapt to local features of an environment remains unclear. To explore this possibility, we recorded the firing of hippocampal neurons in mice navigating virtual reality environments, embedding or not local visual cues (virtual 3D objects) in specific locations. Virtual objects enhanced spatial coding resolution in their vicinity with a higher proportion of place cells, smaller place fields, increased spatial selectivity and stability. This effect was highly dynamic upon objects manipulations. Objects also improved temporal coding resolution through improved theta phase precession and theta timescale spike coordination. We propose that the fast adaptation of hippocampal spatial coding resolution to local features of an environment could be relevant for large-scale navigation.

Abnormal UP/DOWN Membrane Potential Dynamics Coupled with the Neocortical Slow Oscillation in Dentate Granule Cells during the Latent Phase of Temporal Lobe Epilepsy.

The dentate gyrus, a major entry point to the hippocampus, gates (or filters) incoming information from the cortex. During sleep or anesthesia, the slow-wave oscillation (SWO) orchestrates hippocampus-neocortex communication, which is important for memory formation. The dentate gate is altered in temporal lobe epilepsy (TLE) early during epileptogenesis, which favors the propagation of pathological activities. Yet, whether the gating of physiological SWO by dentate granule cells (DGCs) is altered in TLE has remained unexplored. We combined intracellular recordings of membrane potential (V m) of DGCs and local field potential recordings of the SWO in parietal cortex in anesthetized rats early during epileptogenesis [post-status epilepticus (SE) rats]. As expected, in control rats, the V m of DGCs weakly and rarely oscillated in the SWO frequency range. In contrast, in post-SE rats, the V m of DGCs displayed strong and long-lasting SWO. In these cells, clear UP and DOWN states, in phase with the neocortical SWO, led to a bimodal V m distribution. In post-SE rats, the firing of DGCs was increased and more temporally modulated by the neocortical SWO. We conclude that UP/DOWN state dynamics dominate the V m of DGCs and firing early during epileptogenesis. This abnormally strong neocortical influence on the dynamics of DGCs may profoundly modify the hippocampus-neocortex dialogue during sleep and associated cognitive functions.

High- and Low-Order Overtaking-Ability Affordances: Drivers Rely on the Maximum Velocity and Acceleration of Their Cars to Perform Overtaking Maneuvers.

OBJECTIVE: The aim of this study was to answer the question, Do drivers take into account the action boundaries of their car when overtaking? BACKGROUND: The Morice et al. affordance-based approach to visually guided overtaking suggests that the "overtake-ability" affordance can be formalized as the ratio of the "minimum satisfying velocity" (MSV) of the maneuver to the maximum velocity (V(max)) of the driven car. In this definition, however, the maximum acceleration (A(max)) of the vehicle is ignored. We hypothesize that drivers may be sensitive to an affordance redefined with the ratio of the "minimum satisfying acceleration" (MSA) to the A(max) of the car. METHOD: Two groups of nine drivers drove cars differing in their A(max). They were instructed to attempt overtaking maneuvers in 25 situations resulting from the combination of five MSA and five MSV values. RESULTS: When overtaking frequency was expressed as a function of MSV and MSA, maneuvers were found to be initiated differently for the two groups. However, when expressed as a function of MSV/V(max) and MSA/A(max), overtaking frequency was quite similar for both groups. Finally, a multiple regression coefficient analysis demonstrated that overtaking decisions are fully explained by a composite variable comprising MSA/A(max) and the time required to reach MSV. CONCLUSION: Drivers reliably decide whether overtaking is safe (or not) by using low- and high-order variables taking into account their car's maximum velocity and acceleration, respectively, as predicted by "affordance-based control" theory. APPLICATION: Potential applications include the design of overtaking assistance, which should exploit the MSA/A(max) variables in order to suggest perceptually relevant overtaking solutions.

Drivers' decision-making when attempting to cross an intersection results from choice between affordances.

In theory, a safe approach to an intersection implies that drivers can simultaneously manage two scenarios: they either choose to cross or to give way to an oncoming vehicle. In this article we formalize the critical time for safe crossing (CT cross ) and the critical time for safe stopping (CT stop ) to represent crossing and stopping possibilities, respectively. We describe these critical times in terms of affordances and empirically test their respective contribution to the driver's decision-making process. Using a driving simulator, three groups of participants drove cars with identical acceleration capabilities and different braking capabilities. They were asked to try to cross an intersection where there was an oncoming vehicle, if they deemed the maneuver to be safe. If not, they could decide to stop or, as a last resort, make an emergency exit. The intersections were identical among groups. Results showed that although the crossing possibilities (CT cross ) were the same for all groups, there were between-group differences in crossing frequency. This suggests that stopping possibilities (CT stop ) play a role in the driver's decision-making process, in addition to the crossing possibilities. These results can be accounted for by a behavioral model of decision making, and provide support for the hypothesis of choice between affordances.