The coordination of dynamic neural activity within and between neural networks is believed to underlie normal cognitive processes. Conversely, cognitive deficits that occur following neurological insults may result from network discoordination. We hypothesized that cognitive outcome following febrile status epilepticus (FSE) depends on network efficacy within and between fields CA1 and CA3 to dynamically organize cell activity by theta phase. Control and FSE rats were trained to forage or perform an active avoidance spatial task. FSE rats were sorted by those that were able to reach task criterion (FSE-L) and those that could not (FSE-NL). FSE-NL CA1 place cells did not exhibit phase preference in either context and exhibited poor cross-theta interaction between CA1 and CA3. FSE-L and control CA1 place cells exhibited phase preference at peak theta that shifted during active avoidance to the same static phase preference observed in CA3. Temporal coordination of neuronal activity by theta phase may therefore explain variability in cognitive outcome following neurological insults in early development.

Optogenetics holds great promise for both the dissection of neural circuits and the evaluation of theories centered on the temporal organizing properties of oscillations that underpin cognition. To date, no studies have examined the efficacy of optogenetic stimulation for altering hippocampal oscillations in freely moving wild‐type rats, or how these alterations would affect performance on behavioral tasks. Here, we used an AAV virus to express ChR2 in the medial septum (MS) of wild‐type rats, and optically stimulated septal neurons at 6 Hz and 30 Hz. We measured the corresponding effects of these stimulations on the oscillations of the MS and hippocampal subfields CA1 and CA3 in three different contexts: (1) With minimal movement while the rats sat in a confined chamber; (2) Explored a novel open field; and (3) Learned and performed a T‐maze behavioral task. While control yellow light stimulation did not affect oscillations, 6‐Hz blue light septal stimulations altered hippocampal theta oscillations in a manner that depended on the animal's mobility and speed. While the 30 Hz blue light septal stimulations only altered theta frequency in CA1 while the rat had limited mobility, it robustly increased the amplitude of hippocampal signals at 30 Hz in both regions in all three recording contexts. We found that animals were more likely to make a correct choice during Day 1 of T‐maze training during both MS stimulation protocols than during control stimulation, and that improved performance was independent of theta frequency alterations.

Alterations in the voltage-gated sodium channel Nav.1.1 are implicated in various neurological disorders, including epilepsy, Alzheimer’s disease, and autism spectrum disorders. Previous studies suggest that the reduction of Nav1.1 expression leads to a decrease of fast spiking activity in inhibitory neurons. Because interneurons (INs) play a critical role in the temporal organization of neuronal discharge, we hypothesize that Nav1.1 dysfunction will negatively impact neuronal coordination in vivo. Using shRNA interference, we induced a focal Nav1.1 knock-down (KD) in the dorsal region of the right hippocampus of adult rats. Focal, unilateral Nav1.1 KD decreases the performance in a spatial novelty recognition task and the firing rate in INs, but not in pyramidal cells. It reduced theta/gamma coupling of hippocampal oscillations and induced a shift in pyramidal cell theta phase preference. Nav1.1 KD degraded spatial accuracy and temporal coding properties of place cells, such as theta phase precession and compression of ongoing sequences. Aken together, these data demonstrate that a deficit in Nav1.1 alters the temporal coordination of neuronal firing in CA1 and impairs behaviors that rely on the integrity of this network. They highlight the potential contribution of local inhibition in neuronal coordination and its impact on behavior in pathological conditions.

The dentate gyrus is considered to function as an inhibitory gate limiting excitatory input to the hippocampus. Following status epilepticus (SE), this gating function is reduced and granule cells become hyper-excitable. Dentate spikes (DS) are large amplitude potentials observed in the dentate gyrus (DG) of normal animals. DS are associated with membrane depolarization of granule cells, increased activity of hilar interneurons and suppression of CA3 and CA1 pyramidal cell firing. Therefore, DS could act as an anti-excitatory mechanism. Because of the altered gating function of the dentate gyrus following SE, we sought to investigate how DS are affected following pilocarpine-induced SE. Two weeks following lithium-pilocarpine SE induction, hippocampal EEG was recorded in male Sprague-Dawley rats with 16-channel silicon probes under urethane anesthesia. Probes were placed dorso-ventrally to encompass either CA1-CA3 or CA1-DG layers. Large amplitude spikes were detected from EEG recordings and subject to current source density analysis. Probe placement was verified histologically to evaluate the anatomical localization of current sinks and the origin of DS. In 9 of 11 pilocarpine-treated animals and two controls, DS were confirmed with large current sinks in the molecular layer of the dentate gyrus. DS frequency was significantly increased in pilocarpine-treated animals compared to controls. Additionally, in pilocarpine-treated animals, DS displayed current sinks in the outer, middle and/or inner molecular layers. However, there was no difference in the frequency of events when comparing between layers. This suggests that following SE, DS can be generated by input from medial and lateral entorhinal cortex, or within the dentate gyrus. DS were associated with an increase in multiunit activity in the granule cell layer, but no change in CA1. These results suggest that following SE there is an increase in DS activity, potentially arising from hyperexcitability along the hippocampal-entorhinal pathway or within the dentate gyrus itself.

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