Attenuated oscillation of several core clock genes correlates with, and may underlie, aberrant diurnal and circadian rest-activity and sleep-wake patterns observed in Kcna1-null mice. This could contribute to late complications in epilepsy, such as sudden unexpected death in epilepsy. Sirt1 may represent a useful therapeutic target for rescuing circadian clock gene rhythmicity and sleep patterns in epilepsy.

No abstract

Complex neurological conditions can give rise to large scale transcriptomic changes that drive disease progression. It is likely that alterations in one or a few transcription factors or cofactors underlie these transcriptomic alterations. Identifying the driving transcription factors/cofactors is a non-trivial problem and a limiting step in the understanding of neurological disorders. Epilepsy has a prevalence of 1% and is the fourth most common neurological disorder. While a number of anti-seizure drugs exist to treat seizures symptomatically, none is curative or preventive. This reflects a lack of understanding of disease progression. We used a novel systems approach to mine transcriptome profiles of rodent and human epileptic brain samples to identify regulators of transcriptional networks in the epileptic brain. We find that Enhancer of Zeste Homolog 2 (EZH2) regulates differentially expressed genes in epilepsy across multiple rodent models of acquired epilepsy. EZH2 undergoes a prolonged upregulation in the epileptic brain. A transient inhibition of EZH2 immediately after status epilepticus (SE) robustly increases spontaneous seizure burden weeks later. This suggests that EZH2 upregulation is a protective. These findings are the first to characterize a role for EZH2 in opposing epileptogenesis and debut a bioinformatic approach to identify nuclear drivers of complex transcriptional changes in disease.

25Quantification of interictal spikes in EEG may provide insight on epilepsy disease 26 burden, but manual quantification of spikes is time-consuming and subject to bias. We 27 present a probability-based, automated method for the classification and quantification 28 of interictal events, using EEG data from kainate-and saline-injected mice (C57BL/6J 29 background) several weeks post-treatment. We first detected high-amplitude events, 30 then projected event waveforms into Principal Components space and identified 31 clusters of spike morphologies using a Gaussian Mixture Model. We calculated the 32 odds-ratio of events from kainate-versus saline-treated mice within each cluster, 33converted these values to probability scores, P(kainate), and calculated an Hourly 34Epilepsy Index for each animal by summing the probabilities for events where the 35 cluster P(kainate) > 0.5 and dividing the resultant sum by the record duration. This 36 Index is predictive of whether an animal received an epileptogenic treatment (i.e., 37 kainate), even if a seizure was never observed. We applied this method to an out-of-38 sample dataset to assess epileptiform spike morphologies in five kainate mice 39 monitored for ~1 month. The magnitude of the Index increased over time in a subset of 40 animals and revealed changes in the prevalence of epileptiform (P(kainate) > 0.5) spike 41 morphologies. Importantly, in both data sets, animals that had electrographic seizures 42 also had a high Index. This analysis is fast, unbiased, and provides information 43 regarding the salience of spike morphologies for disease progression. Future refinement 44 will allow a better understanding of the definition of interictal spikes in quantitative and 45 unambiguous terms. 46 Epilepsy induction 132During the injection process, when not handled, mice were individually housed in 133 enclosed ~150 cm 3 acrylic cubicles with opaque sides and clear front portals with holes 134 to allow air exchange, and equipped with corn cob bedding and rodent chow. Animals 135 were then randomly assigned to SA or KA treatment, ear punched or tagged for 136 identification and weighed. Mice received a series of intraperitoneal (IP) injections 137 based on the following schedule (herein referred to as "repeated low-dose kainate"). 138

In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is because of a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation, and cognition in the same mice advance our understanding of episodic memory mechanisms and their dysfunction in epilepsy.