Preictal dysfunctions of inhibitory interneurons paradoxically lead to their rebound hyperactivity and to low-voltage-fast onset seizures in Dravet syndrome.

Epilepsies have numerous specific mechanisms. The understanding of neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing therapeutic approaches. We investigated electrographic activities and neural dynamics leading to convulsive seizures in patients and mouse models of Dravet syndrome (DS), a developmental and epileptic encephalopathy in which hypoexcitability of GABAergic neurons is considered to be the main dysfunction. We analyzed EEGs from DS patients carrying a SCN1A pathogenic variant, as well as epidural electrocorticograms, hippocampal local field potentials, and hippocampal single-unit neuronal activities in Scn1a+/- and Scn1aRH/+ DS mice. Strikingly, most seizures had low-voltage-fast onset in both patients and mice, which is thought to be generated by hyperactivity of GABAergic interneurons, the opposite of the main pathological mechanism of DS. Analyzing single-unit recordings, we observed that temporal disorganization of the firing of putative interneurons in the period immediately before the seizure (preictal) precedes the increase of their activity at seizure onset, together with the entire neuronal network. Moreover, we found early signatures of the preictal period in the spectral features of hippocampal and cortical field potential of Scn1a mice and of patients' EEG, which are consistent with the dysfunctions that we observed in single neurons and that allowed seizure prediction. Therefore, the perturbed preictal activity of interneurons leads to their hyperactivity at the onset of generalized seizures, which have low-voltage-fast features that are similar to those observed in other epilepsies and are triggered by hyperactivity of GABAergic neurons. Preictal spectral features may be used as predictive seizure biomarkers.

Stress-induced strain and brain region-specific activation of LINE-1 transposons in adult mice.

Transposable elements (TEs) are conserved mobile genetic elements that are highly abundant in most eukaryotic genomes. Although the exact function of TEs is still largely unknown, it is increasingly clear that they are significantly modulated in response to stress in a wide range of organisms, either directly or indirectly through regulation of epigenetic silencing. We investigated the effect of repeated restraint stress (2 h a day, for 5 d) on transcription levels of LINE-1 (L1) retrotransposon in the brain of inbred BALB/c, DBA/2, C57BL/6N, and outbred CD1 mice. Repeated restraint stress induced strain and brain region-specific modulation of L1 activity. We observed a significant derepression of L1 transcription in the hippocampus (HIPP) of BALB/c mice and a significant downregulation in the hippocampus of C57BL/6N mice. No significant change in L1 expression was found in the other strains and brain regions. These findings indicate in mice the control of transposons expression as an additional mechanism in stress-induced pathophysiological responses, demonstrating that their regulation is highly dependent on the strain genetic background and the brain region. Lay summary Hippocampal expression of the transposon L1 is significantly altered by repeated restraint stress in mice. L1 modulation is not only region specific, but also strain dependent, suggesting that the genetic background is an important determinant of L1 response to environmental stimuli.

RNA polymerase I transcription is modulated by spatial learning in different brain regions.

Long-term memory is accompanied by changes in neuronal morphology and connectivity. These alterations are thought to depend upon new gene expression and protein synthesis over a distributed network of brain structures. Although much evidence supports the idea that the creation of stable, persistent memory traces requires synthesis of new proteins, the role of rRNA transcription and nucleolar activity in learning and memory has hardly been explored. rRNAs needed for protein synthesis result from the activity of two different RNA polymerases, RNA polymerase I and RNA polymerase III, transcribing for 47S RNA and 5S RNA, respectively. In this study, we first investigated the effects of spatial training in the Morris water maze on 47S RNA transcription in the central nervous system, demonstrating bidirectional modulation of its expression over a distributed neural network. We found learning-induced increases in the nucleolar organizer regions in the hippocampus. Finally, we demonstrated that intrahippocampal administrations of CX-5461 (0.6 µg/side), the specific RNA Polymerase I inhibitor, impair the ability of mice to locate the platform in the same task. These results suggest that de novo rRNA transcription is a necessary step for spatial memory consolidation, and that after learning, it occurs in several brain regions with a complex spatiotemporal dynamic. In this study, we demonstrate for the very first time that spatial learning modulates ribosomal RNA transcription in a wide brain circuit, with anatomical specificities in the dynamic of modulation. Together with pharmacological evidences, data presented here support the hypothesis of a necessary role of RNA Pol-I transcription during spatial memory formation. Read the Editorial Highlight for this article on page 673.

Path integration maintains spatial periodicity of grid cell firing in a 1D circular track.

Entorhinal grid cells are thought to provide a 2D spatial metric of the environment. In this study we demonstrate that in a familiar 1D circular track (i.e., a continuous space) grid cells display a novel 1D equidistant firing pattern based on integrated distance rather than travelled distance or time. In addition, field spacing is increased compared to a 2D open field, probably due to a reduced access to the visual cue in the track. This metrical modification is accompanied by a change in LFP theta oscillations, but no change in intrinsic grid cell rhythmicity, or firing activity of entorhinal speed and head-direction cells. These results suggest that in a 1D circular space grid cell spatial selectivity is shaped by path integration processes, while grid scale relies on external information.

Learning induced epigenetic modifications in the ventral striatum are necessary for long-term memory.

Epigenetic modifications such as histone acetylation in cortical or allocortical regions have been shown to be necessary for the formation of long-term memories. Here we investigated whether similar changes were occurring also in the ventral striatum and whether they are necessary for the consolidation of aversive memory. To this purpose we performed immediate post-training focal administrations of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, 5, 10 or 15 µg/side) or the DNA methyltransferase (DNMT) inhibitor, 5-aza-2'-deoxycytidine (5-AZA, 0.0625 or 0.125 µg/side) in the ventral striatum of mice trained in one-trial inhibitory avoidance task. Intra-ventral striatal SAHA administrations, immediately after training, improved memory retention. Opposite effects were found with 5-AZA. We also found that training in the one-trial inhibitory avoidance is accompanied by increased acetylation of specific residues that can be further increased by intra-VS SAHA administrations. Intra-VS 5-AZA administrations on the other hand reduced training-induced histones acetylation at the same residues. These findings imply the occurrence of histone acetylation in the ventral striatum in order to store aversive memory. Moreover, they suggest that the effects induced by the DNMT inhibitor 5-AZA may at least partially due to blockade of H3 and H4 acetylation. These results suggest that the contemporary activation of similar molecular mechanisms might be needed in different brain regions to enable the formation of long-term memories.