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Fear conditioning is an associative learning process by which organisms learn to avoid environmental stimuli that are predictive of aversive outcomes. Fear extinction learning is a process by which avoidance of fear-conditioned stimuli is attenuated when the environmental stimuli is no longer predictive of the aversive outcome. Aberrant fear conditioning and extinction learning are key elements in the development of several anxiety disorders. The 129S1 inbred strain of mice is used as an animal model for maladaptive fear learning because this strain has been shown to generalize fear to other nonaversive stimuli and is less capable of extinguishing fear responses relative to other mouse strains, such as the C57BL/6. Here we report new environmental manipulations that enhance fear and extinction learning, including the ability to discriminate between an aversively paired tone and a neutral tone, in both the 129S1 and C57BL/6 strains of mice. Specifically, we show that discontinuous (“pipped”) tone stimuli significantly enhance within-session extinction learning and the discrimination between neutral and aversively paired stimuli in both strains. Furthermore, we find that extinction training in novel contexts significantly enhances the consolidation and recall of extinction learning for both strains. Cumulatively, these results underscore how environmental changes can be leveraged to ameliorate maladaptive learning in animal models and may advance cognitive and behavioral therapeutic strategies.

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 seizure induction robustly increases spontaneous seizure burden weeks later. Thus, EZH2 upregulation is a protective response mounted after a seizure. 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.Author SummaryEpilepsy is the fourth most common neurological disorder and has been described since the time of Hippocrates. Despite this, no treatments exist to stop epilepsy progression. This is fundamentally due to the complex nature of the disease. Epilepsy is associated with hundreds if not thousands of gene expression changes in the brain that are likely driven by a few key master regulators called transcription factors and cofactors. Finding the aberrantly acting factors is a complex problem that currently lacks a satisfactory solution. We used a novel datamining tool to define key master regulators of gene expression changes across multiple epilepsy models and patient samples. We find that a nuclear enzyme, EZH2, regulates a large number of genes in the rodent and patient epileptic brain and that it’s function is protective. Thus, inhibiting EZH2 greatly exacerbates seizure burden. This is the first report of a novel datamining tool to define drivers of large-scale gene changes and is also the first report of EZH2 induction as an endogenous protective response in the epilepsy.

Histone Deacetylase Inhibitors Restore Normal Hippocampal Synaptic Plasticity and Seizure Threshold in a Mouse Model of Tuberous Sclerosis Complex Basu T, O’Riordan KJ, Schoenike BA, et al. Sci Rep. 2019;9:5266. doi:10.1038/s41598-019-41744-7.Abnormal synaptic plasticity has been implicated in several neurological disorders including epilepsy, dementia, and autism spectrum disorder. Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that manifests with seizures, autism, and cognitive deficits. The abnormal intracellular signaling underlying TSC has been the focus of many studies. However, nothing is known about the role of histone modifications in contributing to the neurological manifestations in TSC. Dynamic regulation of chromatin structure via posttranslational modification of histone tails has been implicated in learning, memory, and synaptic plasticity. Histone acetylation and associated gene activation plays a key role in plasticity and so we asked whether histone acetylation might be dysregulated in TSC. In this study, we report a general reduction in hippocampal histone H3 acetylation levels in a mouse model of TSC2. Pharmacological inhibition of histone deacetylase (HDAC) activity restores histone H3 acetylation levels and ameliorates the aberrant plasticity in TSC2+/− mice. We describe a novel seizure phenotype in TSC2+/− mice that is also normalized with HDAC inhibitors. The results from this study suggest an unanticipated role for chromatin modification in TSC and may inform novel therapeutic strategies for TSC patients.